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408 SECTION 5  •  Virology

AZT must be phosphorylated by host cell enzymes. It lacks or intravenously. Ribavirin is approved for use against HCV
the 3′-hydroxyl necessary for DNA chain elongation and in combination with IFN-α and protease inhibitors. Treat-
prevents complementary DNA synthesis. The selective ment can have serious side effects. 
therapeutic effect of AZT stems from the 100-fold lower sen-
sitivity of the host cell DNA polymerase compared with the OTHER NUCLEOSIDE ANALOGS
HIV reverse transcriptase. Idoxuridine, trifluorothymidine (see Fig. 40.1), and
fluorouracil are analogs of thymidine. These drugs either
Continuous oral AZT treatment is administered to HIV- (1) inhibit the biosynthesis of thymidine, which is a nucleo-
infected people with depleted CD4 T-cell counts to prevent tide essential for DNA synthesis, or (2) replace thymidine
progression of disease. AZT treatment of pregnant HIV- and become incorporated into the viral DNA. These actions
infected women can reduce the likelihood of, or prevent inhibit further synthesis of the virus or cause extensive mis-
transmission of the virus to the baby. Side effects of AZT reading of the genome, leading to mutation and inactiva-
range from nausea to life-threatening bone marrow toxicity. tion of the virus. These drugs target cells in which extensive
DNA replication is taking place, such as those infected with
The high error rate of the HIV polymerase creates exten- HSV, and spare the nongrowing cells from harm.
sive mutations and promotes the development of antiviral
drug-resistant strains. This problem is being addressed by Idoxuridine was the first anti-HSV drug approved for
the administration of multidrug therapy as initial therapy human use but has been replaced by trifluridine and other
(highly active antiretroviral therapy [HAART]). It is more effective, less toxic agents. Fluorouracil is an anti-
more difficult for the HIV to develop resistance to multiple neoplastic drug that kills rapidly growing cells but also has
drugs with multiple target enzymes. Multidrug-resistant been used for topical treatment of warts caused by human
HIV strains are likely to be much weaker than the parent papillomaviruses.
strains. 
Adenine arabinoside was the principal anti-HSV drug
DIDEOXYINOSINE, DIDEOXYCYTIDINE, until ACV was introduced, but it is no longer used because
STAVUDINE, AND LAMIVUDINE of difficulties in administration and toxicity. Ara-A is an
Several other nucleoside analogs have been approved as adenosine nucleoside analog with an arabinose substituted
anti-HIV agents. Dideoxyinosine (didanosine) is a nucleo- for deoxyribose as the sugar moiety (see Fig. 40.1). Many
side analog that is converted to dideoxyadenosine tri- other nucleoside analogs that have antiviral activity are
phosphate (see Fig. 40.1). Similar to AZT, dideoxyinosine, being investigated for clinical use against the herpesviruses,
dideoxycytidine, and stavudine (d4T) lack a 3′-hydroxyl HBV, and HIV.
group. The modified sugar attached to lamivudine
(2′-deoxy-3′-thiacytidine [3TC]) inhibits the HIV reverse Baloxavir marboxil is also a nucleoside analogue
transcriptase by preventing DNA chain elongation and HIV that inhibits the subunit of the influenza polymerase that
replication. Lamivudine and related drugs are also active snatches the cap portion of cellular mRNAs to use as prim-
on the reverse transcriptase polymerase of HBV. Most of the ers for transcription of the viral mRNA. 
anti-HIV agents have potential toxic side effects. 
Nonnucleoside Polymerase
RIBAVIRIN Inhibitors
Ribavirin is an analog of the nucleoside guanosine (see
Fig. 40.1) but differs from guanosine in that its base ring Foscarnet (PFA) and the related PAA are simple com-
is incomplete and open. Similar to other nucleoside ana- pounds that resemble pyrophosphate (Fig. 40.3). These
logs, ribavirin must be phosphorylated. The drug is active drugs inhibit viral replication by binding to the pyrophos-
in vitro against a broad range of viruses. phate-binding site of the DNA polymerase to block nucle-
otide binding. PFA inhibits the DNA polymerase of all
Ribavirin monophosphate resembles guanosine mono-
phosphate and inhibits nucleoside biosynthesis, mRNA NH2 HCl CH3
capping, and other processes important to the replication of CHNH2 HCl
many viruses. Ribavirin depletes the cellular stores of gua-
nine by inhibiting inosine monophosphate dehydrogenase, Amantadine Rimantadine
which is an enzyme important in the synthetic pathway of hydrochloride hydrochloride
guanosine. It also prevents the synthesis of the mRNA 5′
cap by interfering with the guanylation and methylation OH OH
of the nucleic acid base. In addition, ribavirin triphosphate O O
inhibits RNA polymerases and promotes hypermutation of
the viral genome. Its multiple sites of action may explain the HO P C HO P CH2 C
lack of ribavirin-resistant mutants. O OH
O OH
Ribavirin is administered in an aerosol to children with
severe respiratory syncytial virus bronchopneumonia and Phosphonoformic acid Phosphonoacetic acid
potentially to adults with severe influenza or measles. The
drug may be effective for the treatment of influenza B, as well Fig. 40.3  Structures of antiviral drugs.
as Lassa, Rift Valley, Crimean-Congo, Korean, and Argen-
tine hemorrhagic fevers, for which it is administered orally

40  •  Antiviral Agents and Infection Control 409

herpesviruses and the HIV reverse transcriptase without glycoproteins, forming clumps and preventing assembly and
having to be phosphorylated by nucleoside kinases (e.g., virus release. These drugs can be taken prophylactically as
thymidine kinase). PFA and PAA can cause renal and other an alternative to vaccination or, if taken within the first 48
problems because of their ability to chelate divalent metal hours of infection, to reduce the length of illness. Mutations
ions (e.g., calcium) and they become incorporated into in the neuraminidase cause resistance. 
bone. PFA has been approved for the treatment of CMV reti-
nitis in patients with AIDS. Immunomodulators

Nevirapine, delavirdine, efavirenz, and other non- Genetically engineered forms of IFN-α have been approved
nucleoside reverse transcriptase inhibitors bind to sites for human use. Interferons work by binding to cell-surface
on the enzyme different from the substrate. Because these receptors and by initiating a cellular antiviral response. In
drugs’ mechanisms of action differ from those of the nucleo- addition, interferons stimulate the immune response and
side analogs, the mechanism of HIV resistance to the agents promote the immune clearance of viral infection.
is also different. As a result, these drugs are very useful in
combination with nucleoside analogs for the treatment of IFN-α is active against many viral infections. It has been
HIV infection.  approved for the treatment of condyloma acuminatum
(genital warts, a presentation of papillomavirus) and hepa-
Protease Inhibitors titis C (in combination therapy). Attachment of polyethyl-
ene glycol to IFN-α (pegylated IFN-α) increases its potency.
The unique structure of the HIV protease and its essential Pegylated IFN-α can be used with ribavirin to treat hepatitis
role in the production of a functional virion have made C infections. Natural interferon causes the influenza-like
this enzyme a good target for antiviral drugs. Saquinavir, symptoms observed during many viremic and respiratory
indinavir, ritonavir, nelfinavir, and other agents work tract infections, and the synthetic agent has similar side
by slipping into the hydrophobic active site of the enzyme effects during treatment. Interferon is discussed further in
to inhibit its action. Drug-resistant strains arise through Chapters 10 and 37.
mutation of the protease. Use of protease inhibitors signifi-
cantly improved the outcomes for HIV patients. The com- Imiquimod, a Toll-like receptor ligand, stimulates innate
bination of a protease inhibitor with AZT and a second responses to attack the virus infection. This therapeutic
nucleoside analog (HAART) can reduce blood levels of HIV approach can activate local protective responses against
to undetectable levels. papillomas, which generally escape immune control. 

Protease inhibitors (boceprevir, telaprevir, simepre- Infection Control
vir) have also improved the treatment of patients with
chronic hepatitis C.  Infection control is essential in hospital and health care set-
tings. The spread of respiratory viruses is the most difficult to
Antiinfluenza Drugs prevent. Viral spread can be controlled in the following ways:
1. Limiting personnel contact with sources of infection
Amantadine and rimantadine are amphipathic amine
compounds with clinical efficacy against the influenza A (e.g., wearing gloves, mask, goggles; using quarantine)
but not the influenza B virus (see Fig. 40.3). These drugs 2. Improving hygiene, sanitation, and disinfection
have several effects on influenza A replication. Both com- 3. Ensuring that all personnel are immunized against com-
pounds are acidotrophic and concentrate in and buffer the
contents of the endosomal vesicles involved in the uptake mon diseases
of the influenza virus. This effect can inhibit the acid- 4. Educating all personnel regarding points 1, 2, and 3 and
mediated change in conformation in the hemagglutinin
protein that promotes fusion of the viral envelope with cell in the ways to decrease high-risk behaviors
membranes. However, the specificity for influenza A is a Methods for disinfection differ for each virus and depend
result of its ability to bind to and block the proton chan- on its structure. Naked capsid viruses are much more dif-
nel formed by the M2 membrane protein of the influenza A ficult to inactivate than enveloped viruses. Most viruses are
virus. Resistance is the result of an altered M2 or hemag- inactivated by 70% ethanol, 15% chlorine bleach, 2% glu-
glutinin protein. taraldehyde, 4% formaldehyde, or autoclaving (as described
in Guidelines for Prevention of Transmission of Human Immu-
Amantadine and rimantadine may be useful in amelio- nodeficiency Virus and Hepatitis B Virus to Health-Care and
rating an influenza A infection if either agent is taken within Public-Safety Workers, issued in 1989 by the U.S. Centers
48 hours of exposure. They are also useful as a prophylactic for Disease Control and Prevention [CDC]). Most enveloped
treatment in lieu of vaccination. In addition, amantadine is viruses do not require such rigorous treatment and are
an alternative therapy for Parkinson disease. The principal inactivated by soap and detergents. Other means of disin-
toxic effect is on the central nervous system, with patients fection are also available.
experiencing nervousness, irritability, and insomnia. Special “universal” precautions are required for the han-
dling of human blood; that is, all blood should be assumed
Zanamivir (Relenza) and oseltamivir (Tamiflu) inhibit to be contaminated with HIV or HBV and should be handled
influenza A and B as enzyme inhibitors of the neuraminidase with caution. In addition to these procedures, special care
of influenza. Without the neuraminidase to cleave sialic acid, must be taken with syringe needles and surgical tools con-
the hemagglutinin of the virus binds to these sugars on other taminated with blood. Specific guidelines are available from
the CDC.

410 SECTION 5  •  Virology

Control of an outbreak usually requires identification of De Clercq, E., 2011. A 40-year journey in search of selective antiviral
the source or reservoir of the virus, followed by cleanup, quar- c­ hemotherapy. Ann. Rev. Pharmacol. Toxicol. 51, 1–24.
antine, immunization, or a combination of these measures.
The first step in controlling an outbreak of gastroenteritis or Flint, S.J., Racaniello, V.R., et al., 2015. Principles of Virology, fourth ed.
hepatitis A is identification of the food, water, or possibly the American Society for Microbiology Press, Washington, DC.
day-care center that is the source of the outbreak.
Knipe, D.M., Howley, P.M., 2013. Fields Virology, sixth ed. Lippincott Wil-
Education programs can promote compliance with liams & Wilkins, Philadelphia.
immunization programs and help people change lifestyles
associated with viral transmission. Such programs have Richman, D.D., Whitley, R.J., Hayden, F.G., 2017. Clinical Virology,
had a significant effect in reducing the prevalence of vac- fourth ed. American Society for Microbiology Press, Washington, DC.
cine-preventable diseases such as smallpox, polio, measles,
mumps, and rubella. It is hoped that educational programs Richman, D.D., Whitley, R.J., Hayden, F.G., 2009. Clinical Virology, third
will also promote changes in lifestyles and habits to restrict ed. American Society for Microbiology Press, Washington, DC.
the spread of the blood-borne and sexually transmitted HBV
and HIV. Strauss, J.M., Strauss, E.G., 2007. Viruses and Human Diseases, second ed.
Academic, San Diego.
  For questions see StudentC­ onsult.com
Websites
Bibliography New Medical Information, Health Information, Antiviral drugs: antiviral

Cohen, J., Powderly, W.G., 2004. Infectious Diseases, second ed. Mosby, agents, antiviral medications. http://drugs.nmihi.com/antivirals.htm.
St Louis. Accessed June 30, 2018.
U.S. Food and Drug Administration, HBV and HCV. https://www.fda.gov/
ForPatients/Illness/HepatitisBC/ucm408658.htm. Accessed June 30,
2018.
U.S. Food and Drug Administration, HIV Drugs. https://www.fda.gov/
patients/hivaids/hiv-treatment. Accessed 30 June 2019.
U.S. Food and Drug Administration, Influenza (flu) antiviral drugs and
related information. www.fda.gov/Drugs/DrugSafety/InformationbyD
rugClass/ucm100228.htm. Accessed June 30, 2018.

Questions a­ntiinfluenza drug is available and requests therapy.
You tell him that therapy is not appropriate. To what
1 . List the steps in viral replication that are poor targets for therapeutic agents is the patient referring, and why did
antiviral drugs. Why? you decline to use the treatment?
5 . What disinfection procedures are sufficient for inac-
2. Which viruses can be treated with an antiviral drug? tivating the following viruses: HAV, HBV, HSV, and
Distinguish the viruses treatable with an antiviral ­rhinovirus?
nucleoside analog. 6. W hat precautions should health care workers take
to protect themselves from infection with the follow-
3 . A mutation in the gene for which enzymes or proteins ing viruses: HBV, influenza A virus, HSV (whitlow),
would confer resistance to the following antiviral drugs: and HIV?
ACV, phosphonoformate, amantadine, and AZT?

4. A patient has been exposed to influenza A virus and
is in his sixth day of symptoms. He has heard that an

410.e1

41 Papillomaviruses and

Polyomaviruses

A 47-year-old divorced, sexually active woman is seen things. A month later, he has difficulty speaking and
for a routine gynecologic exam. She is a pack-a-day needs assistance with normal daily functions. His
smoker. A Papanicolaou (Pap) smear is performed, mental and physical functions become progressively
and the report indicates high-grade squamous worse. He is treated with cidofovir, and his immu-
intraepithelial lesion (SIL) corresponding to a mod- nosuppressive therapy is eased, but his disease pro-
erate dysplasia and cervical intraepithelial neoplasia gresses to paralysis and he dies. A biopsy of the brain
(CIN) score of 2. Polymerase chain reaction (PCR) shows lesions with sites of demyelination, astrocyto-
analysis indicates that cells in the lesion are infected sis with atypical nuclei, and many histiocytes. PCR
with human papillomavirus 16 (HPV-16). analysis demonstrates the presence of JC polyomavi-
1 . What properties of HPV-16 promote the development of rus in the lesion, confirming a diagnosis of progres-
sive multifocal leukoencephalopathy (PML).
cervical cancer? 5. What properties of JC virus (JCV) promote the develop-
2 . How is the virus transmitted?
3 . What is the nature of the immune response to the virus? ment of PML?
4 . How can transmission and disease be prevented? 6 . Why is this disease also prevalent in individuals with

A 42-year-old man comes to his physician 9 months acquired immunodeficiency syndrome (AIDS)? Who
after a lung transplant, complaining that he has dou- else is at risk for this disease and why?
ble vision, difficulty speaking, feels that his muscles
do not work right, has difficulty with balance, has   Answers to these questions are available on Student
tingling of his hands and feet, and keeps forgetting Consult.com.

Summaries Clinically Significant Organisms

PAPILLOMAVIRUSES ᑏᑏ Warts common; STD ᑏᑏ In immunocompromised people, JCV
ᑏᑏ Asymptomatic transmission, found is activated, spreads to the brain, and
Trigger Words causes PML, which is a conventional
worldwide, no seasonal incidence slow virus disease
HPV, warts, koilocytes, cervical cancer,
STD, CIN Diagnosis ᑏᑏ In PML, JCV partially transforms
ᑏᑏ PCR genome analysis of cervical swabs astrocytes and kills oligodendrocytes,
Biology, Virulence, and Disease causing characteristic lesions and sites
and tissue specimens of demyelination
ᑏᑏ Small naked capsid, DNA genome
ᑏᑏ E6 and E7 proteins inactivate p53 and RB Treatment, Prevention, and Control ᑏᑏ PML lesions are demyelinated, with
ᑏᑏ Vaccine for HPV types 6, 11, 16, 18, 31, unusual large astrocytes and oligoden-
to promote cell growth. droglial cells with very large nuclei
ᑏᑏ Virus is acquired by close contact and 33, 45, 52, and 58
ᑏᑏ BK virus is benign but may cause kidney
infects the epithelial cells of the skin or POLYOMAVIRUSES disease in immunocompromised
mucous membranes patients
ᑏᑏ Tissue tropism and disease presentation Trigger Words
depend on the papillomavirus type ᑏᑏ JCV: PML, opportunistic disease, abnor- Epidemiology
ᑏᑏ Virus persists in the basal layer and then
produces virus in terminally differenti- mal oligodendrocytes, demyelination; ᑏᑏ Transmitted by inhalation or contact
ated keratinocytes BK virus: kidney; MCPyV: Merkel cell with contaminated water or saliva
carcinoma
ᑏᑏ Viruses cause benign outgrowth of cells ᑏᑏ Ubiquitous; immunocompromised
into warts Biology, Virulence, and Disease people at risk for PML by JCV and kidney
ᑏᑏ Small naked capsid, DNA genome damage by BK virus
ᑏᑏ HPV infection is hidden from immune ᑏᑏ T antigen inactivates p53 and RB to
responses and persists ᑏᑏ Found worldwide; no seasonal incidence
promote cell growth
ᑏᑏ Warts resolve slowly but spontaneously, ᑏᑏ Virus infects tonsils and lymphocytes, Diagnosis
possibly as a result of immune response
and spreads by viremia to the kidneys ᑏᑏ JC: Presence of PCR-amplified viral DNA
ᑏᑏ Certain types (HPV-16, HPV-18, etc.) are early in life in cerebrospinal fluid and MRI or CT
associated with cervical, anal, penile, ᑏᑏ Virus is ubiquitous and infections are evidence of lesions
and oropharyngeal cancers asymptomatic
ᑏᑏ Virus establishes persistent and latent Treatment, Prevention, and Control
Epidemiology infection in organs such as kidneys and
lungs ᑏᑏ No modes of control
ᑏᑏ Transmitted by direct contact, sexual
contact (sexually transmitted disease),
fomites, passage through infected birth
canal for laryngeal papillomas (types 6
and 11)

CIN, Cervical intraepithelial neoplasia; CT, computerized tomography; HPV, human papilloma virus; JCV, JC virus; MRI, magnetic resonance imaging; PCR, ­polymerase
chain reaction; PML, progressive multifocal leukoencephalopathy; STD, sexually transmitted disease.

411

412 SECTION 5  •  Virology

What used to be called the papovavirus family (Papova- proteoglycans and other receptors to trigger endocytosis
viridae) has been divided into two families, Papillomaviri- from the cell surface. The early genes of the virus stimu-
dae and Polyomaviridae (Table 41.1). These viruses are late cell growth, which facilitates replication of the viral
capable of causing lytic, chronic, latent, and transforming genome by the host cell DNA polymerase when the cells
infections, depending on the host cell. HPVs cause warts, divide. Binding of the E1 and E2 proteins to viral DNA target
and several genotypes are associated with human cancer cellular replication machinery to the genome. The virus-
(e.g., cervical carcinoma). BK virus (BKV) and JCV, induced increase in cell number causes the basal and the
members of the Polyomaviridae, usually cause asymp- prickle cell layer (stratum spinosum) to thicken (wart, con-
tomatic infection but are associated with renal disease and dyloma, or papilloma). As the basal cell differentiates, the
PML, respectively, in immunosuppressed people. Simian specific nuclear factors expressed in the different layers and
virus 40 (SV40) is the prototype polyomavirus. types of skin and mucosa promote transcription of different
viral genes. Expression of the viral genes correlates with
The papillomaviruses and polyomaviruses are small, the expression of specific keratins. The late genes encoding
nonenveloped, icosahedral capsid viruses with double- the structural proteins are expressed only in the terminally
stranded circular deoxyribonucleic acid (DNA) genomes differentiated upper layer, and the virus assembles in the
(Box 41.1). They encode proteins that promote cell growth. nucleus. As the infected skin cell matures and works its way
The promotion of cell growth facilitates lytic viral repli- to the surface, the virus matures and is shed with the dead
cation in a permissive cell type but may oncogenically cells of the upper layer and takes up to 3 weeks. 
transform a cell that is nonpermissive. The polyoma-
viruses, especially SV40, have been studied extensively as PATHOGENESIS
model oncogenic viruses.
Papillomaviruses infect and replicate in the squamous epi-
Human Papillomaviruses thelium of skin (warts) and mucous membranes (genital,
oral, and conjunctival papillomas) to induce epithe-
STRUCTURE AND REPLICATION lial proliferation. The HPV types are very tissue specific,
HPVs are distinguished and typed by DNA sequence homol- causing different disease presentations. The wart develops
ogy. At least 100 types have been identified and classified because of virus stimulation of cell growth and thickening
into 16 (A through P) groups. HPV can be distinguished of the basal and prickle layers (stratum spinosum), as well
further as cutaneous HPV or mucosal HPV on the basis as the stratum granulosum. Koilocytes, characteristic of
of the susceptible tissue. Within the mucosal HPV, there is a papillomavirus infection, are enlarged keratinocytes with
group associated with cervical, penile, anal, and laryngeal clear halos around shrunken nuclei. It usually takes 3 to
cancer. Viruses in a group cause similar types of warts. 4 weeks to months for the wart to develop (Fig. 41.4). The
viral infection remains local and generally regresses spon-
The icosahedral capsid of HPV is 50 to 55 nm in diam- taneously but can recur. The HPV pathogenic mechanisms
eter and consists of two structural proteins that form 72 are summarized in Box 41.2.
capsomeres (Fig. 41.1). The HPV genome is circular and
has approximately 8000 base pairs. The HPV DNA encodes Innate and cell-mediated immunity are important for
seven or eight early genes (E1 to E8), depending on the control and resolution of HPV infections. HPV can sup-
virus, and two late or structural genes (L1 and L2). An press or hide from protective immune responses. In addi-
upstream regulatory region contains the control sequences tion to very low levels of antigen expression (except in the
for transcription, the shared N-terminal sequence for the
early proteins, and the origin of replication. All the genes BOX 41.1  Unique Properties of
are located on one strand (the plus strand) (Fig. 41.2). Polyomaviruses and Papillomaviruses

The replication cycle of HPV is linked to the life cycle of Papillomavirus: HPV types 1 to 100+ (as determined by geno-
the keratinocyte and epithelial cell of the skin and mucosa. type; types defined by DNA homology, tissue tropism, and asso-
The virus accesses the basal cell layer through breaks in the ciation with oncogenesis)
skin (Fig. 41.3). The L1 protein of HPV is the viral attach-
ment protein and initiates replication by binding to heparin Polyomavirus: SV40, JC virus, BK virus, KI, WU, Merkel cell poly-
omavirus (MCPyV)
TABLE 41.1  Human Papillomaviruses and Small icosahedral capsid virion
Polyomaviruses and Their Diseases Double-stranded circular DNA genome replicated and as-
sembled in nucleus
Virus Disease Viruses have defined tissue tropisms determined by receptor
interactions and transcriptional machinery of cell
Papillomavirus Warts, condylomas, papillomas; cervical, penile, Viruses encode proteins that promote cell growth by binding to
Polyomavirus and anal cancera cellular growth-suppressor proteins p53 and p105RB (p105
retinoblastoma gene product); polyoma T antigen binds to
 BK virus Renal diseaseb p105RB and p53; high-risk papillomavirus E6 protein binds
Progressive multifocal leukoencephalopathyb to p53, activates telomerase, and suppresses apoptosis,
 JC virus and E7 protein binds to p105RB
Viruses can cause lytic infections in permissive cells but cause
 Merkel cell virus Merkel cell carcinoma abortive, persistent, or latent infections or immortalize
(transform) nonpermissive cells
aHigh-risk genotypes are present in 99.7% of these carcinomas.
bDisease occurs in immunosuppressed patients.

41  •  Papillomaviruses and Polyomaviruses 413

Fig. 41.1  Computer reconstruction of cryoelectron micrographs of human papillomavirus (HPV). Left, View of the surface of HPV shows 72 capsomeres
arranged in an icosadeltahedron. All the capsomeres appear to form a regular five-point star shape. Right, Computer cross-section of the capsid shows
the interaction of the capsomeres and channels in the capsid. (From Baker, T.S., Newcomb, W.W., Olson, N.H., et al., 1991. Structures of bovine and human
papillomaviruses. Analysis by cryoelectron microscopy and three-dimensional image reconstruction. Biophys. J. 60, 1445–1456.)

Keratinization Release Replication
Corneum Release
Genome is a double-stranded circular molecule.
Stratum Granulosum Maturation
E1 protein binds DNA at ori and promotes viral DNA replication and Spinosum of virions
has helicase activity (like T antigen of SV40). E2 protein binds DNA,
Genome
helps E1, and activates viral mRNA synthesis. replication

E5 oncoprotein activates the EGF receptor to promote growth.
E4 disrupts cytokeratins to promote release.
E6 and E7 of high-risk strains, e.g., HPV-16 and HPV-18, can become

immortalizing genes and are associated with human cervical cancer.

L1 and L2 gene products are late structural (capsid) proteins.

Enhancer Immortalize, Viral DNA Transcriptional Minor Major Infection
promotor growth replication and replication capsid capsid

origin promoting regulator

E7 E1 E5 L2 Basal Cell proliferation
LCR E6 E2 keratinocytes

L1 Mature virion
Viral DNA
E4

7906/1 1000 2000 3000 4000 5000 6000 7000 Fig. 41.3  Development of a papilloma (wart). Human papillomavirus
infection promotes the outgrowth of the basal layer, increasing the
Fig. 41.2  Genome of human papillomavirus type 16 (HPV-16). number of prickle cells of the stratum spinosum (acanthosis). These
Genomic DNA is normally a double-stranded circular molecule, but it changes cause the skin to thicken and promote the production of kera-
is shown here in a linear form. E5, Oncogene protein that enhances cell tin (hyperkeratosis), causing epithelial spikes to form (papillomatosis).
growth by stabilizing and activating the epidermal growth factor recep- Virus is produced in the granular cells close to the final keratin layer.
tor; E6, oncogene protein that binds p53 and promotes its degradation;
E7, oncogene protein that binds p105RB (p105 retinoblastoma gene High-risk HPV types (e.g., HPV-16, HPV-18; Table
product); EGF, epidermal growth factor; L1, major capsid protein; L2, 41.2) can initiate the development of cervical carci-
minor capsid protein; LCR (URR), long control region (upstream regula- noma and oropharyngeal, esophageal, penile, and anal
tory region); ori, origin of replication. (Courtesy Tom Broker, Baltimore.) cancers. Viral DNA is found in benign and malignant
tumors, especially mucosal papillomas. Almost all cer-
“near-dead” terminally differentiated skin cell), the kerati- vical carcinomas contain integrated HPV DNA,
nocyte is an immunologically privileged site for replication. with 70% from HPV-16 or HPV-18. Breaking of the
Inflammatory responses are required to activate protective circular genome within the E1 or E2 genes to promote
cytolytic responses and promote resolution of warts. Immu- integration causes these genes to be inactivated, pre-
nosuppressed persons have recurrences and more severe venting viral replication without preventing expression
presentations of papillomavirus infections. Antibody to the of other HPV genes, including the E5, E6, and E7 genes
L1 protein neutralizes the virus. IgG produced by vaccina- (Fig. 41.5). The E5, E6, and E7 proteins of HPV-16 and
tion is secreted into the vagina and elsewhere and can pro- HPV-18 have been identified as oncogenes. The E5
tect against infection.

414 SECTION 5  •  Virology

Fig. 41.4  DNA probe analysis of a human papillomavirus 6–induced BOX 41.2  Disease Mechanisms of
anogenital condyloma. A biotin-labeled DNA probe was localized by Papillomaviruses and Polyomaviruses
horseradish peroxidase–conjugated avidin conversion of a substrate to
a chromogen precipitate. Dark staining is seen over the nuclei of koilo- Papillomaviruses
cytotic cells. (From Belshe, R.B., 1991. Textbook of Human Virology, second
ed. Mosby, St Louis, MO.) Virus is acquired by close contact and infects the epithelial cells
of the skin or mucous membranes.
protein enhances cell growth by stabilizing the epidermal
growth factor receptor to make the cell more sensitive Tissue tropism and disease presentation depend on the papillo-
to growth signals, whereas the E6 and E7 proteins bind mavirus type.
and prevent function of the cellular growth-suppressor
(transformation-suppressor) proteins, p53, and the p105 Virus persists in the basal layer and then produces virus in termi-
retinoblastoma gene product (RB). E6 binds the p53 nally differentiated keratinocytes.
protein and targets it for degradation, and E7 binds and
inactivates p105. Enhanced cell growth and inactiva- Viruses cause benign outgrowth of cells into warts.
tion of p53 makes the cell more susceptible to mutation, HPV infection is hidden from immune responses and persists.
chromosomal aberrations, or the action of a cofactor and Warts resolve spontaneously as a result of immune response.
promotes the development of cancer.  Certain types are associated with dysplasia that may become

EPIDEMIOLOGY cancerous with the action of cofactors.
DNA of specific HPV types is present (integrated) in the tumor cell
HPV resists inactivation and can be transmitted on fomites
such as the surfaces of countertops or furniture, bathroom chromosomes. 
floors, and towels (Box 41.3). Asymptomatic shedding may
promote transmission. HPV infection is acquired (1) by Polyomaviruses (JCV and BKV)
direct contact through small breaks in the skin or mucosa,
(2) during sexual intercourse, or (3) while an infant is pass- Virus is acquired through the respiratory or oral route, infects
ing through an infected birth canal. tonsils and lymphocytes, and spreads by viremia to the kidneys
early in life.
Common, plantar, and flat warts are most common in
children and young adults. Laryngeal papillomas occur in Virus is ubiquitous, and infections are asymptomatic.
young children and middle-aged adults. Virus establishes persistent and latent infection in organs such as

HPV only infects humans. It is possibly the most preva- the kidneys and lungs.
lent sexually transmitted infection in the world, with cer- In immunocompromised people, JCV is activated, spreads to
tain HPV types common among sexually active men and
women. At least 79 million people in the United States are the brain, and causes PML, which is a conventional slow virus
infected with HPV, with approximately14 million new ano- disease.
genital cases per year. In PML, JCV partially transforms astrocytes and kills oligodendro-
cytes, causing characteristic lesions and sites of demyelination.
High-risk HPV types, including HPV-16 and HPV-18, PML lesions are demyelinated, with unusual large astrocytes and
are present in oropharyngeal, penile, cervical, vaginal, and oligodendroglial cells with very large nuclei.
anal cancers. According to the Centers for Disease Control BKV is benign but may cause kidney disease in immunocompro-
and Prevention, oropharyngeal squamous cell carcinoma is mised patients.
now the most common HPV-associated cancer.
BKV, BK virus; HPV, human papillomavirus; JCV, JC virus; PML, progressive
HPV is present in 99.7% of all cervical cancers, with multifocal leukoencephalopathy.
HPV-16 and HPV-18 in 70% of them. Other high-risk gen-
otypes are more prevalent in different socioethnic groups. for African American women. Other high-risk strains are
Types 33, 35, 58, and 68 are common high-risk HPV types listed in Table 41.2. Cervical cancer is the second leading
cause of cancer death in women (≈14,000 cases and 4000
deaths per year in the United States).

Approximately 5% of all Pap smears contain HPV-
infected cells, and 10% of women infected with the high-
risk HPV types will develop cervical dysplasia, which is a
precancerous state. Multiple sexual partners, smoking, a
family history of cervical cancer, and immunosuppression
are the major risk factors for infection and progression to
cancer.

HPV-6 and HPV-11 are low-risk HPV types for cervical
carcinoma but cause condyloma acuminatum and oral and
laryngeal papillomas. 

CLINICAL SYNDROMES

The clinical syndromes and the HPV types that cause them
are summarized in Table 41.2.

Warts

A wart is a benign self-limited proliferation of skin that
regresses with time. Most people with HPV infection have
the common types of the virus (HPV-1 through HPV-4),
which infect keratinized surfaces, usually on the hands and
feet (Fig. 41.6). Initial infection occurs in childhood or early

41  •  Papillomaviruses and Polyomaviruses 415

TABLE 41.2  Clinical Syndromes Associated with BOX 41.3  Epidemiology of Polyomaviruses
Papillomaviruses and Papillomaviruses

Syndrome HUMAN PAPILLOMAVIRUS TYPES Disease/Viral Factors
Common Less Common
Capsid virus is resistant to inactivation.
CUTANEOUS SYNDROMES Virus persists in host.
Skin Warts Asymptomatic shedding is likely. 

Plantar wart 1 2, 4 Transmission

Common wart 2, 4 1, 7, 26, 29 Papillomavirus: direct contact, sexual contact (sexually transmit-
ted disease) for certain virus types, or passage through infected
Flat wart 3, 10 27, 28, 41 birth canal for laryngeal papillomas (types 6 and 11)

Epidermodysplasia 5, 8, 17, 20, 9, 12, 14, 15, 19, Polyomavirus: inhalation or contact with contaminated water,
verruciformis 36 21-25, 38, 46 stool, urine, or saliva 

MUCOSAL SYNDROMES Who Is at Risk?
Benign Head and Neck Tumors
Papillomavirus: warts are common; sexually active people at risk
Laryngeal papilloma 6, 11 — for infection with human papillomavirus types correlated with
oral and genital cancers
Oral papilloma 6, 11 2, 16
Polyomavirus: ubiquitous; immunocompromised people at risk
Conjunctival papilloma 11 — for progressive multifocal leukoencephalopathy 

Anogenital Warts Geography/Season

Condyloma acuminatum 6, 11 1, 2, 10, 16, 30, 44, 45 Viruses are found worldwide.
There is no seasonal incidence. 
Cervical intraepithelial 16, 18 31, 33, 35, 39, 45, 51,
neoplasia, cancer (high-risk 52, 56, 58, 59, 66, Modes of Control
types) 68, 69, 73, 82
Vaccine for HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58

Modified from Balows, A., Hausler Jr., W.J., Lennette, E.H. (Eds.), 1988.
Laboratory Diagnosis of Infectious Diseases: Principles and Practice, vol 2.
Springer-Verlag, New York, NY. Data from Centers for Disease Control and
Prevention, 2001. Epidemiology and Prevention of Vaccine-Preventable
Diseases, 12th ed. Public Health Foundation, Washington, DC.

HPV Episomal HPV DNA Integrated HPV DNA
infection and virus production but no virus production
Virus

Squamous epithelium

Basal layer
Basement membrane

Dermis

Normal Cervical intraepithelial Invasive cancer
neoplasia

Fig. 41.5  Progression of human papillomavirus (HPV)–mediated cervical carcinoma. HPV infects and replicates in the epithelial cells of the cervix,
maturing and releasing virus as the epithelial cells progress through terminal differentiation. Growth stimulation of the basal cells produces a wart. In
some cells, the circular genome integrates into host chromosomes, inactivating the E2 gene, which is necessary for replication. Expression of the other
genes without virus production stimulates growth of the cells and possible progression to neoplasia. (Adapted from Woodman, C.B.J., Collins, S.I., Young,
L.S., 2007. The natural history of cervical HPV infection: unresolved issues. Nat. Rev. Cancer 7, 11–22.)

416 SECTION 5  •  Virology

Fig. 41.7  Papanicolaou stain of exfoliated cervicovaginal squamous
epithelial cells, showing the perinuclear cytoplasmic vacuolization
termed koilocytosis (vacuolated cytoplasm), which is characteristic of
human papillomavirus infection (400× magnification).

Fig. 41.6  Common warts. (From Habif, T.P., 1985. Clinical Dermatology: appear as soft, flesh-colored warts that are flat, raised,
A Color Guide to Diagnosis and Therapy. Mosby, St Louis, MO.) and sometimes cauliflower shaped. The warts can
appear within weeks or months of sexual contact with
adolescence. The incubation period before a wart develops an infected person. Cytologic changes indicating HPV
may be as long as 3 to 4 months. The appearance of the infection (koilocytotic cells) are detected in Papani-
wart (dome shaped, flat, or plantar) depends on the HPV colaou-stained cervical smears (Pap smears) (Fig.
type and the infected site.  41.7). Infection of the female genital tract by high-risk
Head and Neck Papillomas and Tumors HPV types is associated with intraepithelial cervical
Single oral papillomas are the most benign epithelial neoplasia and cancer. The first neoplastic changes are
tumors of the oral cavity. They are pedunculated with termed dysplasia. Approximately 40% to 70% of the
a fibrovascular stalk, and their surface usually has a mild dysplasias spontaneously regress.
rough, papillary appearance. They can occur in people
of any age group, are usually solitary, and rarely recur Cervical cancer is thought to develop through a con-
after surgical excision. Laryngeal papillomas are tinuum of progressive cellular changes from mild (CIN 1)
commonly associated with HPV-6 and HPV-11 and are to moderate neoplasia (CIN 2) to severe neoplasia or car-
the most common benign epithelial tumors of the lar- cinoma in situ (Fig. 41.8; see Fig. 41.5). This sequence of
ynx. Infection of children probably occurs at birth and events can occur over 1 to 4 years. Routine and regular Pap
can be life-threatening if the papillomas obstruct the smears can promote early detection, treatment, and cure of
airway. Occasionally, papillomas may be found farther cervical cancer. 
down in the trachea and into the bronchi. As many as
80% of oropharyngeal carcinomas contain high-risk LABORATORY DIAGNOSIS
HPV DNA.  A wart can be confirmed microscopically on the basis of
Anogenital Warts its characteristic histologic appearance, which consists of
Anogenital warts (condylomata acuminata) occur hyperplasia of the prickle cells and an excess production
almost exclusively on the squamous epithelium of the of keratin (hyperkeratosis). Papillomavirus infection can
external genitalia and perianal areas and are common for be detected in Pap smears by the presence of koilocytotic
promiscuous individuals. Approximately 90% are caused (vacuolated cytoplasm) squamous epithelial cells, which
by HPV-6 and HPV-11. Anogenital lesions infected with are rounded and occur in clumps (Fig. 41.4; and Fig. 41.7).
these types of HPV can be problematic but rarely become DNA molecular probe, PCR, and real-time PCR analy-
malignant in otherwise healthy people. Anal and penile sis of cervical swabs and tissue specimens are the methods
warts can progress to cancer if caused by high-risk onco- of choice for establishing the diagnosis and typing of the
genic strains of HPV.  HPV infection. Papillomaviruses do not grow in cell cul-
Cervical Dysplasia and Neoplasia tures, and tests for HPV antibodies are rarely used except in
HPV infection of the genital tract is a very common sexu- research studies. 
ally transmitted disease. Infection is usually asymptom-
atic but may result in slight itching. Genital warts may TREATMENT, PREVENTION, AND CONTROL
Warts spontaneously regress, but the regression may take
many months to years. Warts are removed because of
pain and discomfort, for cosmetic reasons, and to prevent
spread to other parts of the body or to other people. They
are removed through the use of surgical cryotherapy,

41  •  Papillomaviruses and Polyomaviruses 417

Within 1 year 1–3 years Up to decades Polyomaviridae
Persistent CIN 2/3 Cervical
infection cancer The human polyomaviruses, BKV and JCV, are ubiquitous
but usually do not cause disease. Less prevalent human
Initial HPV CIN 1* polyomaviruses include the KI, WU, and Merkel cell poly-
infection omaviruses (MCVs). The human viruses are difficult to
grow in cell culture. SV40 (a simian polyomavirus) and
Clear infection murine polyomaviruses, in particular, have been studied
extensively as models of tumor-causing viruses, but only
*CIN: cervical intraepithelial neoplasia recently has a polyomavirus been associated with human
cancers.
Fig. 41.8  Progression of high-risk HPV infection to cervical carcinoma.
Most HPV infections resolve spontaneously, but the virus can establish STRUCTURE AND REPLICATION
a persistent infection that can progress to low-grade cervical intraepi- The polyomaviruses are smaller (45 nm in diameter),
thelial neoplasia (CIN 1). This may resolve or progress directly to a contain less nucleic acid (5000 base pairs), and are less
higher grade CIN (CIN2 or CIN3) and if untreated progress to cervical complex than the papillomaviruses (see Box 41.1). The
cancer. (Adapted from https://www.cdc.gov/vaccines/pubs/pinkbook/ genomes of BKV, JCV, and SV40 are closely related and are
hpv.html.) divided into early, late, and noncoding regions (Fig. 41.9).
The early region on one strand codes for nonstructural T
TABLE 41.3  Laboratory Diagnosis of Papillomavirus (transformation) proteins (including large T, T′, and
Infections small t antigens), and the late region, which is on the
other strand, codes for three viral capsid proteins (VP1,
Test Detects VP2, and VP3) (Box 41.4). The noncoding region contains
the origin of DNA replication and transcriptional control
Cytology Koilocytotic cells sequences for both early and late genes.
In situ DNA probe analysis Viral nucleic acid
PCRa Viral nucleic acid For JCV infection of glial cells, the virus binds to
Real-time PCR Viral nucleic acid sialylated carbohydrates and serotonin receptors and
Culture Not useful then enters the cell by endocytosis. The DNA genome is
uncoated and delivered to the nucleus. The early genes
aMethod of choice. encode the large T and small t antigens, which are proteins
PCR, Polymerase chain reaction. that promote cell growth. Viral replication requires the
transcriptional and DNA replication machinery provided
electrocautery, or chemical means (e.g., 10% to 25% solu- by a growing cell. The large T antigens of SV40, BKV, and
tion of podophyllin), although recurrences are common. JCV have several functions. For example, the T antigen of
Surgery may be necessary for the removal of laryngeal SV40 binds to DNA and controls early and late gene tran-
papillomas. scription, as well as viral DNA replication. In addition, the
T antigen binds to and inactivates the two major cellular
Stimulators of innate and inflammatory responses, growth-suppressor proteins, p53 and p105RB, promoting
such as imiquimod (Aldara), interferon, and even cell growth.
stripping off duct tape, can promote more rapid healing.
Topical or intralesional delivery of cidofovir can treat Similar to replication of the HPVs, replication of poly-
warts by selectively killing the HPV-infected cells. Cido- omavirus is highly dependent on host cell factors. Permis-
fovir induces apoptosis by inhibiting the host cell DNA sive cells allow the transcription of late viral messenger
polymerase. ribonucleic acid (mRNA) and viral replication, which
results in cell death. Immune factors can promote a block
Immunization with a nine-valent (Gardasil 9: 6, 11, in replication causing the virus to establish latency in these
16, 18, 31, 33, 45, 52, and 58) HPV vaccine is recom- nonpermissive cells. Some animal cells allow only the early
mended for girls and boys starting at age 11 years (before genes, including the T antigen, to be expressed, promoting
sexual activity) to prevent cervical cancer and penile and cell growth and potentially leading to oncogenic transfor-
anogenital warts. A bivalent (Cervarix) and a tetravalent mation of the cell.
vaccine (Gardasil) are no longer offered in the United
States. In 2018 the U.S. Food and Drug Administration The polyomavirus genome is used very efficiently. The
approved immunization of adults aged 27 to 45. These noncoding region of the genome contains the initiation sites
vaccines consist of the L1 major capsid protein assem- for the early and late mRNAs and the origin of DNA repli-
bled into virus-like particles. Vaccinated women are not cation. The three late proteins are produced from mRNAs,
protected against all possible high-risk HPV strains. The which have the same initiation site and then are processed
HPV vaccine is not a replacement for a Pap smear, into three unique mRNAs.
and women should continue to be tested. At present,
the best way to prevent transmission of warts is to avoid The circular viral DNA is maintained and replicated bidi-
coming in direct contact with infected tissue. Proper pre- rectionally, similar to the way a bacterial plasmid is main-
cautions (e.g., use of condoms) can prevent sexual trans- tained and replicated. DNA replication precedes late mRNA
mission of HPV.  transcription and protein synthesis. The virus is assembled
in the nucleus and is released by cell lysis. 

418 SECTION 5  •  Virology

Early Late JC/BK Oral or Replication Primary Multiplication
mRNA mRNA viruses respiratory in oral, GI, viremia in kidney
or upper Transient
infection respiratory secondary
viremia
tracts

Latent Immunocompetent
indefinitely
0.6 ori 0.7 in kidney
0.5 0.8
VVPP32 Viruria and BK virus IMMUNO-
0.4 0.9 possible multiplies SUPPRESSION
in urinary
hemorrhagic Reactivation
cystitis tract JC virus viremia

0.3 1.0/0 CNS
0.1
0.2 VP1 Possible PML

Large T Fig. 41.10  Mechanisms of spread of polyomaviruses within the body.
antigen CNS, Central nervous system; GI, gastrointestinal; PML, progressive mul-
tifocal leukoencephalopathy.

Fig. 41.9  Genome of the SV40 virus. The genome is a prototype of of astrocytes results in partial transformation, yielding
other polyomaviruses and contains early, late, and noncoding regions. enlarged cells with abnormal nuclei resembling glioblasto-
The noncoding region contains the start sequence for the early and mas. Productive lytic infections of oligodendrocytes cause
late genes and for DNA replication (ori). The individual early and late demyelination. Although SV40, BKV, and JCV can cause
mRNAs are processed from the larger nested transcripts. (Modified from tumors in hamsters, these viruses are not associated with
Butel, J.S., Jarvis, D.L., 1986. The plasma-membrane-associated form of any human tumors. Integration and a mutation of the
SV40 large tumor antigen: biochemical and biological properties. Biochim. T antigen that prevents replication of the MCV allow this
Biophys. Acta 865, 171–195.) virus to convert the cell into a tumor. 

BOX 41.4  Polyomavirus Proteins EPIDEMIOLOGY
Polyomavirus infections are ubiquitous, and most people
Early are infected with both JCV and BKV by the age of 15 years
Large T: regulation of early and late messenger RNA transcription; (see Box 41.3). The viruses are spread in urine, in feces, and
potentially in aerosols. Latent infections can be reactivated
DNA replication; cell growth promotion and transformation in people whose immune systems are suppressed because of
Small t: viral DNA replication  AIDS, organ transplantation, or pregnancy. Approximately
Late 10% of people with AIDS develop PML, and the disease is
VP1: major capsid protein and viral attachment protein fatal in approximately 90% of all cases. The incidence has
VP2: minor capsid protein decreased with the success of the highly active antiretrovi-
VP3: minor capsid protein ral therapy (HAART).

PATHOGENESIS Early batches of live attenuated polio vaccine were con-
taminated with SV40 that was undetected in the primary
Each polyomavirus is limited to specific hosts and cell monkey cell cultures used to prepare the vaccine. Although
types within that host. For example, JCV and BKV are many people were vaccinated with the contaminated vac-
human viruses that probably enter the respiratory tract or cines, no SV40-related tumors have been reported. 
tonsils, after which they infect lymphocytes and then the
kidney with a minimal cytopathologic effect. BKV estab- CLINICAL SYNDROMES
lishes latent infection in the kidney, and JCV establishes Primary infection is almost always asymptomatic (Box
infection in the kidneys, B cells, monocyte-lineage cells, 41.5). BKV and JCV can be activated in immunocompro-
and other cells. Replication is blocked in immunocompe- mised patients, as indicated by the presence of virus in the
tent persons. urine of as many as 40% of these patients. The viruses are
also reactivated during pregnancy, but no effects on the
In T-cell–deficient patients, such as those with the fetus have been noted. During pregnancy, cell-mediated
acquired immunodeficiency syndrome (AIDS), reactiva- immunity, including those activities that restrict the repli-
tion of the virus in the kidney leads to viral shedding in the cation of polyomaviruses, are suppressed so that the fetus (a
urine and potentially severe urinary tract infections (BKV) tissue graft) is not rejected.
or viremia and central nervous system infection (JCV) (Fig.
41.10). JCV crosses the blood-brain barrier by replicating
in the endothelial cells of capillaries. An abortive infection

41  •  Papillomaviruses and Polyomaviruses 419

BOX 41.5  Clinical Summaries Clinical Case 41.1 Progressive
Multifocal Leukoencephalopathy
Wart: A 22-year-old patient develops a conical, flesh-colored, (PML)
hard, scaly round area (papule) over the index finger. It has
a rough surface and is nontender. Otherwise, the patient is Liptai and associates (Neuropediatrics 38:32–35, 2007)
healthy and has no other complaints. The wart is treated topi- described a case in which a 15½-year-old human immuno-
cally on a daily basis with salicylic acid to kill the cells harboring deficiency virus (HIV)–infected boy presented with fatigue
the virus and remove the wart. and depression. Symptoms included dizziness, double
vision, and loss of motor coordination, as indicated in his
Cervical papilloma: On cervical examination, a large, flat papule handwriting, computer usage, and unsteady gait. He had
was observed, which turned white with application of 4% acquired HIV as an infant by injection with an unclean
acetic acid. The Pap smear from this 25-year-old sexually active syringe needle in a Transylvanian hospital. Over the years,
woman had koilocytotic cells. his CD4 T-cell count slowly decreased, and his HIV genome
load increased, most likely because of poor compliance
Cervical carcinoma: A 32-year-old woman comes in for her with his anti-HIV therapy and a refusal of highly active
routine Pap smear, which shows evidence of abnormal cells. A antiretroviral therapy. A 30-mm nonenhancing lesion of
biopsy shows squamous cell carcinoma. PCR analysis of cellular the right cerebellar hemisphere was seen by magnetic reso-
DNA yields HPV-16 DNA. nance imaging. PML was diagnosed, based on detection
of JC virus sequences in cerebrospinal fluid by polymerase
PML: A 42-year-old AIDS patient has become forgetful and has chain reaction. Within 10 days, the boy lost the ability to
difficulty speaking, seeing, and keeping his balance, which is walk and developed facial and hypoglossal palsies, with
suggestive of lesions in many sites in the brain. The condition further neurologic deterioration, including severe depres-
progresses to paralysis and death. Autopsy shows foci of demy- sion and loss of ability to communicate. He died 4 months
elination, with oligodendrocytes containing inclusion bodies after the onset of symptoms. Microscopic analysis of the
only in the white matter. cerebellum and brainstem indicated broad areas of demy-
elination and necrosis, astrocytosis, and oligodendrocytes
A 37-year-old woman with multiple sclerosis was treated with with nuclear inclusion bodies. Although JC virus infection
natalizumab and interferon-β and developed PML. is ubiquitous and normally benign, it only causes PML in
immunocompromised individuals. Previously rare, PML
HPV, Human papillomavirus; Pap, Papanicolaou; PCR, polymerase chain has become more prevalent because of increased numbers
reaction; PML, progressive multifocal leukoencephalopathy. of immunocompromised individuals including acquired
immunodeficiency syndrome patients who are not on or
The ureteral stenosis observed in renal transplant recipi- are not compliant with anti-HIV therapy or for whom anti-
ents appears to be associated with BKV, as is the hem- HIV therapy is ineffective.
orrhagic cystitis observed in bone marrow transplant
recipients. PML caused by JCV is a subacute demyelinat- PML, Progressive multifocal leukoencephalopathy.
ing disease that occurs in immunocompromised patients,
including those with AIDS (Clinical Case 41.1). Immu- the particular genetic sequences can also be used to detect
notherapy that inhibits the α4-integrin adhesion protein virus. Urine cytologic tests can reveal the presence of JCV
(natalizumab) also increases risk for PML. Although rare, or BKV infection by revealing the existence of enlarged cells
the incidence of PML has increased because of the increased with dense basophilic intranuclear inclusions resembling
numbers of people with AIDS and immunosuppressive those induced by cytomegalovirus. It is difficult to isolate
therapy. As the name implies, patients may have multiple BKV and JCV in tissue cultures; therefore this procedure is
neurologic symptoms unattributable to a single anatomic not attempted. 
lesion. Speech, vision, coordination, mentation, or a combi- TREATMENT, PREVENTION, AND CONTROL
nation of these functions is impaired, followed by paralysis Decreasing the immunosuppression responsible for allow-
of the arms and legs and finally death. People who are diag- ing the polyomavirus to be reactivated is the best treatment
nosed with PML live 1 to 4 months, and most die within 2 for JC and BK viruses. Cidofovir may also be helpful. The
years. ubiquitous nature of polyomaviruses and the lack of under-
standing of their modes of transmission make it unlikely
The genome of a new polyomavirus, MCV (or MCPyV), that the primary infection can be prevented.
was recently discovered integrated into the chromatin of
Merkel cell carcinomas, which is a highly aggressive type   For a case study and questions see StudentC­ onsult.com
of skin cancer. This is the first example of a polyomavirus
associated with a human cancer.  Bibliography

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Case Study and Questions 3 . What viral, cellular, and host conditions regulate the
replication of this virus and other HPVs?
A 25-year-old carpenter notices the appearance of several
hyperkeratotic papules (warts) on the palm side of his index 4. How would the papillomavirus type causing this infec-
finger. They do not change in size and cause him only mini- tion be identified?
mal discomfort. After a year, they spontaneously disappear.
1. Will this virus infection spread to other body sites? 5 . Is it likely that this type of HPV is associated with human
2. After its disappearance, is the infection likely to be com- cancer? If not, which types are associated with cancers,
and which cancers are they?
pletely resolved or to persist in the host?

420.e1

42 Adenoviruses

A 19-year-old army recruit complained that he had a 3. What other diseases can adenoviruses cause?
high fever, chills, cough, runny nose, and sore throat. 4. What type of immune response would protect against
Several other members of his unit complained of sim-
ilar symptoms. infection?
1. How is adenovirus transmitted? 5. Why did the military develop an attenuated vaccine for
2 . Which adenovirus types are most likely to cause acute
adenovirus strains 4 and 7?
respiratory distress syndrome?
 Answers to these questions are available on Student
Consult.com.

Summaries Clinically Significant Organisms

ADENOVIRUSES ᑏᑏ E1A and E1B proteins inactivate E6 and Epidemiology
E7 to promote growth ᑏᑏ Transmitted by aerosols, direct contact,
Trigger Words
ᑏᑏ Virus encodes polymerase fecal-oral, contaminated swimming pools
Pharyngitis, conjunctivitis, atypical pneu- ᑏᑏ Capsid virus resistant to inactivation Diagnosis
monia, icosadeltahedral capsid ᑏᑏ Lytic virus ᑏᑏ Immunological assays and PCR genome
ᑏᑏ Causes pharyngitis, conjunctivitis, atypi-
Biology, Virulence, and Disease analysis
cal pneumonia, infantile gastroenteritis, Treatment, Prevention, and Control
ᑏᑏ Medium-sized icosadeltahedral capsid acute respiratory disease ᑏᑏ Adenovirus types 4 and 7 vaccine only
with fibers, linear DNA genome with ᑏᑏ Can be used as vector for making vac-
terminal proteins cines and gene therapy for military

Adenoviruses were first isolated in 1953 in a human ade- enough to encode 30 to 40 genes. The adenovirus genome
noid cell culture. Since then, approximately 100 serotypes is a linear double-stranded DNA with a terminal pro-
have been recognized, at least 52 of which infect humans. tein (molecular mass, 55 kDa) covalently attached at each
All human serotypes are included in a single genus within 5′ end. The virions have a unique structure. The nonenvel-
the family Adenoviridae. There are seven subgroups for oped icosadeltahedral capsid comprises 240 capsomeres
human adenoviruses (A through G) (Table 42.1). The that consist of hexons and pentons and has a diameter of 70
viruses in each subgroup share many properties. to 90 nm (Fig. 42.1 and Box 42.1). The 12 pentons, which
are located at each of the vertices, have a penton base and a
The human adenoviruses numbered 1 to 7 are the most fiber. The fiber contains the viral attachment proteins.
common. Common disorders caused by the adenoviruses The penton base and fiber are toxic to cells. The pentons
include respiratory tract infection, pharyngocon- and fibers also carry type-specific antigens.
junctivitis (pinkeye), hemorrhagic cystitis, and gas-
troenteritis. Immunocompromised individuals are at risk The core complex within the capsid includes viral DNA
for more serious presentations. Several adenoviruses have and at least two major proteins. There are at least 11 pro-
oncogenic potential in animals but not humans, and for this teins in the adenovirus virion, 9 of which have an identified
reason they have been extensively studied by molecular biol- structural function (Table 42.2).
ogists. These studies have elucidated many viral and eukary-
otic cellular processes. For example, analysis of the gene for The virus replication cycle takes approximately 32 to 36
the adenovirus hexon protein led to the discovery of introns hours and produces approximately 10,000 virions. Attach-
and the splicing of eukaryotic messenger ribonucleic acid ment of the viral fiber proteins to a glycoprotein member of
(mRNA). Adenovirus is also being used in genetic therapies the immunoglobulin superfamily of proteins (≈100,000 fiber
to deliver deoxyribonucleic acid (DNA) for gene replacement receptors are present on each cell) initiates infection for most
and modification therapy (e.g., cystic fibrosis) to express adenoviruses. This same receptor is used by many coxsacki-
genes for other viruses (e.g., human immunodeficiency virus evirus B viruses; thus it is given the name coxsackie ade-
[HIV]) as a vaccine, and as oncolytic therapy. novirus receptor. Some adenoviruses use the class I major
histocompatibility complex (MHC I) molecule as a receptor.
Structure and Replication Internalization is initiated by the interaction of the penton
base with an αv integrin followed by receptor-mediated endo-
Adenoviruses are double-stranded DNA viruses with a cytosis in a clathrin-coated vesicle. The virus lyses the endo-
genome of approximately 36,000 base pairs, which is large somal vesicle, and the capsid delivers the DNA genome to the
nucleus. The penton and fiber proteins of the capsid are toxic
to the cell and can inhibit cellular macromolecular synthesis.

421

422 SECTION 5  •  Virology

Table 42.1  Illnesses Associated with Adenoviruses

Disease Types Patient Population
1, 3, 5, 7, 14, 21, etc.
RESPIRATORY DISEASES Infants, young children
Febrile, undifferentiated upper respiratory tract infection Children, adults
Infants, young children, military recruits
Pharyngitis and pharyngoconjunctival fever 1, 2, 3, 4, 5, 6, 7, 14 Infants, young children
Infants, young children, military recruits,
Acute respiratory disease 1, 2, 3, 4, 5, 6, 7, 14, 21
immunocompromised patients
Pertussis-like syndrome 1, 2, 3, 4, 7, 14, 21, 30
Children, immunocompromised patients
Pneumonia Any age
Infants, young children, immunocompromised patients
OTHER DISEASES 11, 21 Infants, young children
Acute hemorrhagic cystitis/nephritis 8, 9, 11, 19, 35, 37 Immunocompromised patients
Epidemic keratoconjunctivitis 31, 40, 41, 52 Children, immunocompromised patients
Gastroenteritis 11, 21, 34, 35 Children
Hemorrhagic cystitis 1, 2, 5, 7, 31 Any age
Hepatitis 7
Meningoencephalitis 7, 21
Myocarditis 31
Obesity/adipogenesis

Adenovirus

AB

Fig. 42.1  (A) Electron micrograph of adenovirus virion with fibers. (B) Model of adenovirus virion with fibers. (A, From Valentine, R.C., Pereira, H.G., 1965.
Antigens and structure of the adenovirus. J. Mol. Biol. 13, 13–20. B, From Cohen, J., Powderly, W.G., Opal, S.M., 2010. Infectious Diseases, third ed. Mosby, Phila-
delphia, PA.)

A map of the adenovirus genome shows the locations of polymerase and proteins that promote cell growth and
the viral genes (Fig. 42.2). The genes are transcribed from suppress apoptosis and host immune and inflammatory
both DNA strands and in both directions at different times responses.
during the replication cycle. Genes for related functions
are clustered together. Most of the RNA transcribed from Transcription of mRNA occurs in two phases. Early pro-
the adenovirus genome is processed into several individual teins promote cell growth and include a DNA polymerase
mRNAs in the nucleus. Adenovirus encodes its own DNA that is involved in the replication of the genome. As for the
papovaviruses, several adenovirus mRNAs are transcribed

42  •  Adenoviruses 423

BOX 42.1  Unique Features of Adenovirus L1 L2 L3 L4 L5

Naked icosadeltahedral capsid has fibers (viral attachment E1B E3
proteins) at vertices.
E1A 5Ј
Linear double-stranded genome has 5′ terminal proteins. r strand 3Ј 3Ј
Synthesis of viral DNA polymerase activates a switch from early to E2A E4
l strand 5Ј
late genes.
Virus encodes its own DNA polymerase and other proteins to E2B

facilitate growth and immune escape. Late genes Early genes
Human adenoviruses are grouped A through G by DNA homolo-
Introns removed by RNA processing
gies and by serotype (>55 human types).
Serotype is mainly a result of differences in the penton base and Fig. 42.2  Simplified genome map of adenovirus type 2. Genes are
transcribed from both strands (l and r) in opposite directions. The early
fiber protein, which determine the nature of tissue tropism and genes are transcribed from four promoter sequences, and each gen-
disease. erates several messenger RNAs by processing the primary RNA tran-
Virus causes lytic, persistent, and latent infections in humans, scripts. This produces the full repertoire of viral proteins. The splicing
and some strains can immortalize certain animal cells. pattern for only the E2 transcript is shown as an example. All of the late
genes are transcribed from one promoter sequence. E, Early protein; L,
Table 42.2  Major Adenovirus Proteins late protein. (Modified from Jawetz, E., Adelberg, E.A., Melnick, J.L., 1987.
Review of Medical Microbiology, 17th ed. Appleton & Lange, Norwalk, CT.)

Gene Molecular
Number Mass (kDa) Functions of Proteins

E1Aa — — Activates viral gene transcription from the same promoter and share initial sequences but are
Binds cellular growth suppres- produced through the splicing out of different introns. Tran-
E1B — — scription of the early E1 gene, processing of the primary
sor (p105RB) to promote cell transcript (splicing out of introns to yield three mRNAs),
E2 — — growth and transformation and translation of the immediate early E1A transactiva-
Deregulates cell growth tor protein are required for transcription of early proteins.
E3 — — Inhibits activation of interferon The early proteins include more DNA-binding proteins, the
— response elements DNA polymerase, and proteins to help the virus escape the
E4 — — immune response. The E1A protein together with the E1B
VA RNAs — 120 Binds cellular growth suppressor protein can stimulate cell growth by binding to the cellular
Capsid II 85 (p53) to promote cell growth growth-suppressor proteins p105RB (p105RB retinoblas-
62 and transformation toma gene product) (E1A) and p53 (E1B). In permissive
III cells, stimulation of cell division facilitates transcription and
Blocks apoptosis replication of the genome, with cell death resulting from
IV virus replication. In nonpermissive cells, the virus estab-
Activates some promoters lishes latency, and the genome remains in the nucleus. For
VI 24 Terminal protein on DNA rodent, not human, cells, the E1A and E1B proteins may
VIII 13 DNA polymerase promote cell growth but without cell death; therefore the
IX 12 virus oncogenically transforms the cell.
IIIa 66 Prevents TNF-α action; MHC I
Core V 48 expression Viral DNA replication occurs in the nucleus and is medi-
ated by the viral-encoded DNA polymerase. The poly-
VII 18 Limits viral cytopathologic effect merase uses the 55-kDa viral protein (terminal protein)
with an attached cytosine monophosphate as a primer to
Inhibits interferon response replicate both strands of the DNA. The terminal protein
remains attached to the DNA.
Contains family antigen and
some serotyping antigens Late gene transcription starts after DNA replication. Most
of the individual late mRNAs are generated from a large
Penton base protein (83% of the genome) primary RNA transcript that is pro-
Toxic to tissue culture cells cessed into at least 18 individual mRNAs.

Fiber Capsid proteins are produced in the cytoplasm and then
Responsible for attachment; transported to the nucleus for viral assembly. Empty pro-
capsids first assemble, and then the viral DNA and core
contains some serotyping proteins enter the capsid through an opening at one of the
antigens vertices. The replication and assembly processes are inef-
ficient and prone to error, producing as few as one infec-
Hexon-associated proteins tious unit per 2300 particles. DNA, protein, and numerous
defective particles accumulate in nuclear inclusion bodies.
Penton-associated proteins The virus remains in the cell and is released when the cell
degenerates and lyses. 
“Capsid cement” nonessential

“Facilitates assembly”

Core protein 1: DNA-binding
protein

Core protein 2: DNA-binding
protein

aEarly genes encode several messenger RNAs and proteins by alternative
splicing patterns.

E, Early; MHC I, major histocompatibility complex I; RB, retinoblastoma gene
product; TNF-α, tumor necrosis factor-α; VA, virus-associated.

424 SECTION 5  •  Virology BOX 42.3  Epidemiology of Adenoviruses

BOX 42.2  Disease Mechanisms of Disease/Viral Factors
Adenoviruses
Capsid virus is resistant to inactivation by gastrointestinal tract,
Virus is spread in aerosols, in fecal matter, and by close contact. drying, and detergents.
Fingers spread virus to eyes.
Disease symptoms may resemble those of other respiratory virus
Virus infects mucoepithelial cells in the respiratory tract, gastro- infections.
intestinal tract, and conjunctiva or cornea, causing cell damage
directly. Virus may cause asymptomatic shedding. 

Disease is determined by the tissue tropism of the specific group Transmission
or serotype of the virus strain.
Direct contact, respiratory droplets and fecal matter on hands and
Virus persists in lymphoid tissue (e.g., tonsils, adenoids, Peyer fomites (e.g., towels, contaminated medical instruments), and
patches). inadequately chlorinated swimming pools and ponds 

Antibody is important for prophylaxis and resolution, but cell- Who Is at Risk?
mediated immunity is also important.
Children <14 years of age
People in crowded areas (e.g., day-care centers, military training

camps, swimming clubs) 

Geography/Season

Virus is found worldwide.
There is no seasonal incidence. 

Modes of Control

Live vaccine for serotypes 4 and 7 is available for military use.

Fig. 42.3  Histologic appearance of adenovirus-infected cells. Ineffi- Although certain adenoviruses (groups A and B) are onco-
cient assembly of virions yields dark basophilic nuclear inclusion bod- genic in certain rodents, adenovirus transformation of
ies containing DNA, proteins, and capsids. human cells has not been observed.

Pathogenesis and Immunity Innate responses limit the initial spread of the virus and
activate protective NK and T-cell responses. Cell-mediated
Adenoviruses are capable of causing lytic (e.g., mucoepi- immunity is important in limiting virus outgrowth, and
thelial cells), latent (e.g., macrophage, T cells, adenoid cells immunosuppressed people suffer more serious and recur-
and other cells), and transforming (hamster, not human) rent disease. Antibody is important for resolving lytic
infections. These viruses initially infect epithelial cells lining adenovirus infections and protects the person from rein-
the oropharynx, as well as the respiratory and enteric organs fection with the same serotype but not other serotypes.
(Box 42.2). The viral fiber proteins determine the target cell Neutralizing antibody is directed at the fiber proteins.
specificity. The toxic activity of the penton base protein can Adenoviruses have several mechanisms to evade host
result in the inhibition of cellular mRNA transport and pro- defenses and help them persist in the host. They encode
tein synthesis, cell rounding, and tissue damage. small virus-associated RNAs (VA RNAs) that prevent
activation of the interferon-induced protein kinase R–
The histologic hallmark of adenovirus infection is a dense, mediated inhibition of viral protein synthesis. The viral
central intranuclear inclusion (that consists of viral DNA and E3 and E1A proteins block apoptosis induced by cellular
protein) within an infected epithelial cell (Fig. 42.3). These responses to the virus or by T-cell or cytokine (e.g., tumor
inclusions may resemble those seen in cells infected with necrosis factor [TNF]-α) actions. Some strains of adenovi-
­cytomegalovirus, but adenovirus does not cause cellular ruses can inhibit CD8+ cytotoxic T-cell action by prevent-
enlargement (cytomegaly). Mononuclear cell infiltrates and ing proper expression of MHC I molecules and therefore
epithelial cell necrosis are seen at the site of infection. antigen presentation. 

Initial infection occurs to the pharynx, conjunctiva, or Epidemiology
upper respiratory tract for most types and then spreads to
lymph nodes and possibly the lower respiratory tract. The Adenovirus virions resist drying, detergents, gastrointesti-
infection may resolve or the virus may become latent and nal tract secretions (acid, protease, and bile), and even mild
persist in lymphoid and other tissue such as adenoids, ton- chlorine treatment (Box 42.3). These virions are spread in
sils, and Peyer patches, and can be reactivated in immu- aerosols and by the fecal-oral route, by fingers, by fomites
nosuppressed patients. Viremia may occur after local (including towels and medical instruments), and in ponds
replication of the virus, with subsequent spread to visceral or poorly chlorinated swimming pools. Crowds and close
organs. This dissemination is more likely to occur in immu- proximity, as occurs in classrooms and military barracks,
nocompromised patients than in immunocompetent ones. promotes spread of the virus. Adenoviruses may be shed
intermittently and over long periods from the pharynx
and especially in feces. Most infections are asymptomatic,

42  •  Adenoviruses 425

BOX 42.4  Clinical Summaries Clinical Case 42.1 Pathogenic
Adenovirus 14
Pharyngoconjunctival fever: A 7-year-old student develops sud-
den onset of red eyes, sore throat, and a fever of 38.9° C (102° F). The Centers for Disease Control and Prevention (MMWR
Several children in the local elementary school have similar 56:1181–1184, 2007) reported that analysis of isolates
symptoms. from trainees during an outbreak of febrile respiratory
infection at Lackland Air Force Base showed 63% resulting
Gastroenteritis: An infant has diarrhea and is vomiting. Adeno- from adenovirus, and 90% of these were adenovirus 14.
virus serotype 41 is identified by polymerase chain reaction Of the 423 cases, 27 were hospitalized with pneumonia, 5
analysis of stool for epidemiologic reasons. required admission to the intensive care unit, and 1 patient
died. In an analogous case reported by CNN (www.cnn.c
Contagious om/2007/HEALTH/conditions/12/19/killer.cold/index.
html), an 18-year-old high school athlete complained of
Virus in respiratory secretions flulike symptoms with vomiting, chills, and fever of 104°
F that progressed to life-threatening pneumonia within
Virus in stool days. The adenovirus causing these infections is a mutant
of the adenovirus 14, which was first identified in 1955.
Viremia may occur The adenovirus 14 mutant has spread around the United
States, putting adults at risk for severe disease. Adenovirus
Symptoms Specific 14 infection usually causes a benign respiratory infection
antibody in adults, with newborns and the elderly at higher risk for
present severe outcomes. Although most virus mutations produce
a weaker virus, occasionally a more virulent antibody-
escape or antiviral drug–resistant virus may occur.

Incubation period

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 21 infection. Affected patients have mild, flulike symptoms
Days (including nasal congestion, cough, coryza, malaise, fever,
chills, myalgia, and headache) that may last 3 to 5 days.
Inoculation of Pharyngoconjunctival fever occurs more often in outbreaks
respiratory involving older children.
epithelial cells
ACUTE RESPIRATORY DISEASE
Fig. 42.4  Time course of adenovirus respiratory infection. Acute respiratory disease is a syndrome consisting of fever,
runny nose, cough, pharyngitis, and possible conjunctivi-
which is a feature that greatly facilitates their spread in the tis (Clinical Case 42.1). The high incidence of infection of
community. military recruits stimulated the development and use of a
vaccine for serotypes 4 and 7. 
Adenoviruses 1 through 7 are the most prevalent sero-
types. From 5% to 10% of cases of pediatric respiratory OTHER RESPIRATORY TRACT DISEASES
tract disease are caused by adenovirus types 1, 2, 5, and 6, Adenoviruses cause coldlike symptoms, laryngitis, croup,
and the infected children shed virus for months after infec- and bronchiolitis. They can also cause a pertussis-like ill-
tion. Adenovirus causes 15% of the cases of gastroenteritis ness in children and adults that consists of a prolonged clin-
requiring hospitalization. Serotypes 4 and 7 seem especially ical course and true viral pneumonia. 
able to spread among military recruits because of their close
proximity and rigorous lifestyle. Immunosuppressed indi- CONJUNCTIVITIS AND EPIDEMIC
viduals are at highest risk to serious disease.  KERATOCONJUNCTIVITIS
Adenoviruses cause follicular conjunctivitis (pinkeye)
Clinical Syndromes in which the mucosa of the palpebral conjunctiva becomes
pebbled or nodular, and both conjunctivae (palpebral and
Adenoviruses primarily infect children and, less commonly, bulbar) become inflamed (Fig. 42.5). Such conjunctivitis
adults (Box 42.4). Disease from reactivated virus occurs in may occur sporadically or in outbreaks that can be traced
immunocompromised children and adults. Specific clinical to a common source. Swimming pool conjunctivitis is a
syndromes are associated with specific adenovirus types familiar example of a common-source adenovirus infection.
(see Table 42.1). The time course of adenovirus respiratory Epidemic keratoconjunctivitis may be an occupational
infection is shown in Fig. 42.4.  hazard for industrial workers. The most striking such epi-
demic occurred in people working in the naval shipyards
ACUTE FEBRILE PHARYNGITIS AND of Pearl Harbor in Hawaii, in which it caused more than
PHARYNGOCONJUNCTIVAL FEVER 10,000 cases during 1941 and 1942. Irritation of the eye
Adenovirus causes pharyngitis, which is often accompa-
nied by conjunctivitis (pharyngoconjunctival fever).
Pharyngitis alone occurs in young children, particularly
those younger than 3 years, and may mimic streptococcal

426 SECTION 5  •  Virology

Fig. 42.5  Conjunctivitis caused by adenovirus. Direct analysis of the clinical sample without virus isola-
tion can be used for rapid detection and identification of ade-
by a foreign body, dust, debris, and so forth is a risk factor noviruses. Immunoassays (e.g., fluorescent antibody and
for acquisition of this infection.  enzyme-linked immunosorbent assay) and genome assays
GASTROENTERITIS AND DIARRHEA (e.g., different variations of polymerase chain reaction [PCR]
Adenovirus is a major cause of acute viral gastroenteritis, and DNA probe analysis) can be used to detect, type, and
especially in infants. The enteric adenoviruses (types 40 to group the virus in clinical samples and tissue cultures. These
42) do not replicate in the same tissue culture cells as do approaches must be used for enteric adenovirus serotypes 40
other adenoviruses and rarely cause fever or respiratory to 42, which do not grow readily in available cell cultures.
tract symptoms.  Serologic testing is rarely used except for epidemiologic
OTHER MANIFESTATIONS purposes.
Adenovirus has also been associated with intussusception
in young children, acute hemorrhagic cystitis with dysuria The isolation of most adenovirus types is best accom-
and hematuria in young boys, musculoskeletal disorders, plished in cell cultures derived from epithelial cells (e.g.,
and genital and skin infections. Adenovirus (type 36) is also primary human embryonic kidney cells, continuous [trans-
associated with obesity.  formed] lines, such as HeLa and human epidermal carci-
SYSTEMIC INFECTION IN IMMUNOCOMPROMISED noma cells). Within 2 to 20 days, the virus causes a lytic
PATIENTS infection with characteristic inclusion bodies and cell death.
Immunocompromised patients, especially those deficient Recovery of virus from cell culture requires an average of 6
in T-cell function, are at risk for serious adenovirus infec- days. The characteristic intranuclear inclusions can be seen
tions. Adenoviral disease in immunocompromised patients in infected tissue during histologic examination. However,
includes pneumonia, acute diarrhea, hepatitis, and life- such inclusions are rare and must be distinguished from
threatening systemic disease affecting multiple organs. those produced by cytomegalovirus. 
Infection can originate from infection or reactivation from
latency.  Treatment, Prevention, and
Control
Laboratory Diagnosis
Careful handwashing and chlorination of swimming
For the results of virus isolation to be significant, the isolate pools can reduce transmission of adenovirus. There is no
should be obtained from a site or secretion relevant to the approved treatment for routine adenovirus infections.
disease symptoms. The presence of adenovirus in the throat Cidofovir and also ribavirin can be used to treat adenovi-
of a patient with pharyngitis is usually diagnostic if labora- rus-infected immunosuppressed individuals. Live oral vac-
tory findings eliminate other common causes of pharyngi- cines have been used to prevent infections with adenovirus
tis, such as Streptococcus pyogenes. types 4 and 7 in military recruits but are not used in civilian
populations.

Therapeutic Adenoviruses

Adenoviruses have been used and are being considered for
gene delivery for correction of human diseases, including
immune deficiencies (e.g., adenosine deaminase deficiency),
cystic fibrosis, and lysosomal storage diseases. The virus is
inactivated by deletion or mutation of the E1 and other
viral genes (e.g., E2, E4). The appropriate gene is inserted
into the viral genome, replacing this DNA, and it is con-
trolled by an appropriate promoter. The resultant virus vec-
tor must be grown in a cell that expresses the missing viral
functions (E1, E4) to complement the deficiency and allow
production of virus. Types 4 and 7 and replication defective
mutants of types 5, 26, and 35 are being developed to carry
genes of HIV, Ebola, and other viruses as hybrid attenuated
vaccines for these deadly viruses. Oncolytic therapy can be
provided by adenoviruses lacking a functional E1B gene,
which selectively grows and kills tumor cells that lack a
functional p53 protein. Despite the genetically engineered
attenuation, these viruses still may cause serious disease in
immunocompromised individuals.
  For a case study and questions see StudentConsult.com.

42  •  Adenoviruses 427

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Case Study and Questions 3 . What physical properties of the virus facilitate its trans-
mission?
A 7-year-old boy attending summer camp complains of
sore throat, headache, cough, red eyes, and tiredness and 4 . What precautions should the camp owners take to pre-
is sent to the infirmary. His temperature is 40° C. Within vent other outbreaks?
hours, other campers and counselors visit the infirmary
with similar symptoms. Symptoms last for 5 to 7 days. All 5 . What sample or samples would have been used by the
the patients have gone swimming in the camp pond. More Public Health Department to identify the infectious
than 50% of the people in the camp complain of symptoms agent, and what tests would be required to diagnose the
similar to those in the initial case. The Public Health Depart- infection?
ment identifies the agent as adenovirus serotype 3.
1. Toward which adenovirus syndrome do the symptoms

point?
2. An outbreak as large as this indicates a common source

of infection. What was the most likely source or sources?
What were the most likely routes by which the virus was
spread?

427.e1

43 Human Herpesviruses

(a) A vesicular lesion erupts at the corner of a cytomegalovirus (CMV) pneumonitis, and sub-
27-year-old man’s mouth 3 days after return- sequently an Epstein-Barr virus (EBV)–related
ing from a skiing trip. lymphoma. The lymphoma resolved after immu-
nosuppressive therapy was decreased.
( b) A 26-year-old pediatric medical resident develops 1. Which viruses cause these diseases?
serious pneumonia, and then vesicular lesions 2 . What features are similar/different for these viruses?
erupt in crops on his head, trunk, and elsewhere. 3. How were each of these infections obtained?
4. What are the risk factors for serious herpes disease?
(c) S everal high school cheerleaders developed a 5. Which of the infections can be prevented by vaccine or
sore throat, fever, swollen glands, and were very treated with antiviral drugs?
tired. They shared a water bottle at a football
game three weeks earlier.   Answers to these questions are available on Student
Consult.com.
(d) A 57-year-old heart transplant recipient had an
outbreak of herpes simplex virus (HSV) lesions,

Summaries Clinically Significant Organisms

HERPESVIRUSES ᑏᑏ Encodes polymerase and other proteins Epidemiology
(HSV and VZV: thymidine kinase) ᑏᑏ Ubiquitous viruses
Trigger Words ᑏᑏ Transmitted by direct contact, bodily fluids
ᑏᑏ Cell-mediated immune response essential ᑏᑏ VZV transmitted by aerosol and direct
ᑏᑏ HSV-1 and HSV-2: neurotropic, Cowdry for control
type A inclusion bodies, syncytia, vesicle, contact
Tzanck smear ᑏᑏ Lytic, latent, recurrent infections; EBV and
HHV-8 also associated with cancers Diagnosis
ᑏᑏ VZV: neurotropic, (V) all stages of lesions, ᑏᑏ Culture, immunologic tests
(Z) lesions along single dermatome ᑏᑏ HSV: oral/genital, encephalitis, kerato-
conjunctivitis, neonatal HSV; recurs from (EBV serology), PCR and genome
ᑏᑏ EBV: lymphotropic: B cell, heterophile-posi- neurons analysis
tive mononucleosis, Burkitt lymphoma
ᑏᑏ VZV: pneumonia in adults, varicella, zoster; Treatment, Prevention, and Control
ᑏᑏ CMV: large cell and owl’s eye inclusion recurs from neurons ᑏᑏ Vaccines for varicella and zoster
body, opportunistic, mononucleosis, con- ᑏᑏ Antiviral drugs for HSV, VZV, and CMV
genital disease ᑏᑏ EBV: heterophile-positive mononucleosis,
B-cell lymphomas; recurs from memory
ᑏᑏ and HHV7: lymphotropic, roseola B cell
ᑏᑏ HHV-8: Kaposi sarcoma, AIDS-related disease
ᑏᑏ B virus: monkey, fatal encephalopathy ᑏᑏ CMV: opportunistic disease, congenital
CMV, retinitis; recurs from monocyte and
Biology, Virulence, and Disease stem cell

ᑏᑏ Large, enveloped, icosadeltahedral capsid, ᑏᑏ HHV-6: roseola
DNA genome ᑏᑏ HHV-8: Kaposi sarcoma

CMV, Cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpesvirus; HSV, herpes simplex virus; PCR, polymerase chain reaction; VZV, varicella-zoster virus.

The herpesviruses are an important group of large deoxy- tissue tropism, cytopathologic effect, and site of latent infec-
ribonucleic acid (DNA)–enveloped viruses with the follow- tion), as well as the pathogenesis of the disease and disease
ing features in common: virion morphology, basic mode of manifestation (Table 43.1). HHVs are HSV types 1 and 2
replication, and capacity to establish latent and recurrent (HSV-1 and HSV-2), VZV, EBV, CMV, HHV-6 and HHV-7,
infections. Cell-mediated immunity is important for causing and HHV-8.
symptoms and controlling infection with these viruses. Her-
pesviruses encode proteins and enzymes that facilitate rep- Herpesvirus infections are common, and the viruses,
lication and interaction of the virus with the host. EBV and except HHV-8, are ubiquitous. Although these viruses
human herpesvirus 8 (HHV-8) are associated with human usually cause benign disease, especially in children, they
cancers (Box 43.1). can also cause significant morbidity and mortality, espe-
cially in immunosuppressed people. Fortunately, some her-
HHVs are grouped into three subfamilies on the basis pesviruses encode targets for antiviral agents, and there are
of differences in viral characteristics (genome structure, vaccines for VZV.

428

43  •  Human Herpesviruses 429

Structure of Herpesviruses 43.2). Direct or inverted repeat sequences bracket
unique regions of the genome (unique long [UL], unique
The herpesviruses are large, enveloped viruses that con- short [US]), allowing circularization and recombination
tain double-stranded DNA. The virion is approximately within the genome. Recombination among inverted
150 nm in diameter and has the characteristic morphol- repeats of HSV, CMV, and VZV allows large portions of
ogy shown in Fig. 43.1. The DNA core is surrounded by the genome to flip the orientation of their UL and US gene
an icosadeltahedral capsid containing 162 capso- segments with respect to each other to form isomeric
meres. This capsid is enclosed by a glycoprotein-contain- genomes. 
ing envelope. Herpesviruses encode several glycoproteins
for viral attachment, fusion, and escaping immune con- Herpesvirus Replication
trol. Attached to the capsid and in the space between the
envelope and the capsid (the tegument) are viral proteins Herpesvirus replication is initiated by the interaction of
and enzymes that help initiate replication. As enveloped viral glycoproteins with cell-surface receptors (see Fig.
viruses, the herpesviruses are sensitive to acid, solvents, 36.11). The tropism of some herpesviruses (e.g., EBV) is
detergents, and drying. highly restricted because of the species and tissue-specific
expression of their receptors. Viral glycoproteins facili-
Herpesviral genomes are linear, double-stranded tate the fusion of its envelope with the plasma membrane,
DNA, but they differ in size and gene orientation (Fig. releasing the nucleocapsid into the cytoplasm. Enzymes
and transcription factors are carried into the cell in the
BOX 43.1  Unique Features of tegument of the virion. The nucleocapsid docks with
Herpesviruses the nuclear membrane and delivers the genome into
the nucleus, in which the genome is transcribed and
Have large, enveloped, icosadeltahedral capsids containing replicated.
double-stranded DNA genomes.
Transcription of the viral genome and viral protein syn-
Encode many proteins that manipulate the host cell and immune thesis proceeds in a coordinated and regulated manner in
response. three phases:
1 . Immediate early proteins (α), consisting of proteins
Encode enzymes (DNA polymerase) that promote viral DNA repli-
cation and are good targets for antiviral drugs. important for the regulation of gene transcription and
takeover of the cell
DNA replication and capsid assembly occurs in the nucleus. 2 . Early proteins (β), consisting of more transcription
Virus is released by exocytosis, by cell lysis, and through cell-to- factors and enzymes, including the DNA polymerase
3 . Late proteins (γ), consisting mainly of structural pro-
cell bridges. teins, which are generated after viral genome replica-
Can cause lytic, persistent, latent, and (for Epstein-Barr virus) im- tion has begun

mortalizing infections.
Ubiquitous.
Cell-mediated immunity is required for control.

TABLE 43.1  Properties Distinguishing the Herpesviruses

Subfamily Virus Primary Target Cell Site of Latency Means of Spread

ALPHAHERPESVIRINAE Mucoepithelial cells
Mucoepithelial cells
HHV-1 Herpes simplex type 1 Mucoepithelial and T cells Neuron Close contact (STD)
Neuron Close contact (STD)
HHV-2 Herpes simplex type 2 B cells and epithelial cells Neuron Respiratory and close contact
Lymphocytes and ?
HHV-3 Varicella-zoster virus
Macrophages, lymphocytes,
GAMMAHERPESVIRINAE epithelial cells, and ?

HHV-4 Epstein-Barr virus T lymphocytes, epithelial Memory B cell Saliva (kissing disease)
cells, neuronal cells B cell Close contact (sexual), saliva
HHV-8 Kaposi sarcoma–related virus
Like HHV-6
BETAHERPESVIRINAE

HHV-5 Cytomegalovirus HPC, myeloid stem Close contact (STD), transfusions, tissue
cell, monocyte transplant, and congenital
HHV-6 HHV-6
HPC, T cells Saliva

HHV-7 HHV-7 HPC and T cell Saliva

HHV, Human herpesvirus; HPC, hematopoietic progenitor cells STD, sexually transmitted disease; ?, indicates that other cells may also be the primary target or
site of latency.

430 SECTION 5  •  Virology

Schematic structure of herpes group viruses

Viral glycoproteins Capsomere
Envelope (protein subunit)

Capsid

Capsid

A B DNA core

Fig. 43.1  (A) Electron micrograph and (B) general structure of the herpesviruses. The DNA genome of the herpesvirus in the core is surrounded by
an icosadeltahedral capsid and an envelope. Glycoproteins are inserted into the envelope. (A, From Cohen, J., Powderly, W.G., Opal, S.M., 2010. Infectious
Diseases, third ed. Mosby, Philadelphia, PA.)

Herpesvirus UL US Number of The viral genome is transcribed by the cellular DNA-
genomes UL US isomeric dependent ribonucleic acid (RNA) polymerase and is regu-
VZV U3 lated by viral-encoded and cellular nuclear factors. The
U4 U5 forms interplay of these factors determines whether a lytic, per-
HSV-1, U1 U2 2 sistent, or latent infection occurs. Cells that promote latent
HSV-2 4 infection transcribe a special set of viral genes without
genome replication. Progression to early and late gene expres-
EBV 1 sion results in virus production and usually cell death.

HHV-8 UL 1 The viral-encoded DNA polymerase, which is a target of
CMV UL US 4 antiviral drugs, replicates the viral genome. Viral-encoded
scavenging enzymes provide deoxyribonucleotide sub-
HHV-6 1 strates for the polymerase. These and other viral enzymes
facilitate replication of the virus in nongrowing cells that
0 50 100 150 lack sufficient deoxyribonucleotides and enzymes for viral
Molecular weight ϫ 106 DNA synthesis (e.g., neurons). Other proteins manipulate
cellular machinery to optimize replication, inhibit immune
Fig. 43.2  Herpesvirus genomes. The genomes of herpesviruses are responses, and inhibit apoptosis or establish latency.
doubled-stranded DNA. The length and complexity of the genome
differ for each virus. Inverted repeats in herpes simplex virus (HSV), Empty procapsids assemble in the nucleus, are filled
varicella-zoster virus (VZV), and cytomegalovirus (CMV) allow the with DNA, bud into and out of the endoplasmic reticulum
genome to recombine with itself to form isomers. Large genetic repeat (ER), acquire tegument-associated proteins and bud into
sequences are boxed. The genomes of HSV and CMV have two sections, the Golgi membrane to acquire their envelope, and exit
the unique long (UL) and the unique short (US), each of which is brack- the cell by exocytosis or by lysis of the cell. Transcription,
eted by two sets of inverted repeats of DNA. The inverted repeats facili- protein synthesis, glycoprotein processing, and exocytotic
tate the replication of the genome and also allow the UL and US regions release from the cell are performed by cellular machinery.
to invert independently of each other to yield four different genomic During replication, herpesviruses disrupt cellular processes,
configurations, or isomers. VZV has only one set of inverted repeats and degrade cellular DNA, and alter the cytoskeleton of the
can form two isomers. Epstein-Barr virus (EBV) exists in only one config- cells. The replication of HSV is discussed in more detail as
uration, with several unique regions surrounded by direct repeats. Blue the prototype of the herpesviruses. 
bars indicate direct repeat DNA sequences; green bars indicate inverted
repeated DNA sequences. HHV-6, Human herpesvirus 6; HHV-8, human Herpes Simplex Virus
herpesvirus 8.
The name herpes is derived from a Greek word meaning “to
creep.” “Cold sores” were described in antiquity, and their
viral etiology was established in 1919.

43  •  Human Herpesviruses 431

The two types of HSVs, HSV-1 and HSV-2, share many promote replication. Other early proteins inhibit produc-
characteristics, including DNA homology, antigenic deter- tion and initiate degradation of cellular messenger RNA
minants, tissue tropism, and disease signs. However, they (mRNA) and DNA. Expression of the early and late genes
can still be distinguished by subtle but significant differ- generally leads to cell death.
ences in these properties.
The genome is replicated as soon as the polymerase is
HERPES SIMPLEX VIRUS PROTEINS synthesized. Circular end-to-end concatemeric forms of the
The HSV genome is large enough to encode approximately genome are made initially. Later in the infection, the DNA
80 proteins. Only half the proteins are required for viral rep- is replicated by a rolling-circle mechanism to produce a
lication; the others facilitate HSV’s interaction with differ- linear string of genomes that, in theory, resemble a roll of
ent host cells and the immune response. The HSV genome toilet paper. The concatemers are cleaved into individual
encodes enzymes that include a DNA-dependent DNA genomes as the DNA is sucked into a procapsid.
polymerase and scavenging enzymes such as deoxyribo-
nuclease, thymidine kinase, ribonucleotide reductase, and Genome replication triggers transcription of the late
protease. Ribonucleotide reductase converts ribonucleo- genes from which structural and other proteins are encoded.
tides to deoxyribonucleotides, and thymidine kinase phos- Many copies of the structural proteins are required. The
phorylates the deoxyribonucleosides to provide substrates capsid proteins are then transported to the nucleus, in
for replication of the viral genome. The substrate specifici- which they are assembled into empty procapsids and filled
ties of these enzymes and the DNA polymerase are less selec- with DNA. DNA-containing capsids associate with viral
tive than those of their cellular analogs and thus represent protein-disrupted nuclear membranes and bud into and
potentially good targets for antiviral chemotherapy. then out of the ER into the cytoplasm. The viral glycopro-
teins are synthesized and processed like cellular glycopro-
HSV encodes at least 10 glycoproteins that serve as viral teins. Tegument proteins associate with the viral capsid
attachment proteins (gB, gC, gD, gE/gI), fusion proteins (gB, in the cytoplasm, and then the capsid buds into a portion
gH/gL), structural proteins, immune escape proteins (gC, of the trans-Golgi network to acquire their glycoprotein-
gE, gI), and provide other functions.  containing envelope. The virus is released by exocytosis or
cell lysis. Virus can also spread between cells through intra-
REPLICATION cellular bridges, which allows the virus to escape antibody
HSV can infect most types of human cells, and even cells of detection. Virus-induced syncytia formation also spreads
other species. The virus generally causes lytic infections of the infection.
fibroblasts and epithelial cells and latent infections of neu-
rons (see Fig. 36.11, for a diagram). HSV infection of neurons may result in virus replica-
tion or establishment of latency, depending on which viral
HSV-1 binds quickly and efficiently to cells through an genes the neuron is capable of transcribing. Transcription
initial interaction with heparan sulfate, which is a proteo- of the LAT and no other viral gene will result in latency.
glycan found on the outside of many cell types, and then As for other alphaherpesviruses, HSV encodes a thymidine
through a tighter interaction with receptor proteins at the kinase (scavenging enzyme) to facilitate replication in non-
cell surface. Penetration into the cell requires interaction dividing cells such as neurons. HSV also encodes ICP34.5,
with nectin-1 (herpesvirus entry mediator C), which is an which is a protein unique to HSV, that has multiple func-
intercellular adhesion molecule that is a member of the tions to facilitate virus growth in neurons and neuroinva-
immunoglobulin protein family and similar to the poliovi- sive disease. ICP34.5 removes a block to protein synthesis
rus receptor. Nectin-1 is found on most cells and neurons. activated in response to virus infection or as part of the anti-
Another receptor is HveA, which is a member of the tumor viral response of type 1 interferons, inhibits autophagy, and
necrosis factor receptor family expressed on activated T promotes release of capsids from the nucleus and virus at
cells, neurons, and other cells. HSV can penetrate the host cell–cell junctions. 
cell by fusion of its envelope with the cell-surface mem-
brane. On fusion, the virion releases its capsid into the cyto- PATHOGENESIS AND IMMUNITY
plasm, along with a protein that promotes the initiation The mechanisms involved in the pathogenesis of HSV-1
of viral gene transcription, a viral-encoded protein kinase, and HSV-2 are very similar (Box 43.2). Both viruses ini-
and cytotoxic proteins. The capsid docks with a nuclear tially infect, replicate in mucoepithelial cells, cause disease
pore and delivers the genome into the nucleus. at the site of infection, and then establish latent infection of
the innervating neurons. HSV-1 and HSV-2 differ in growth
The immediate early gene products include DNA- characteristics and antigenicity, and HSV-1 has a greater
binding proteins that stimulate DNA synthesis and promote potential to cause encephalitis, whereas HSV-2 has a
transcription of the early viral genes. During a latent infec- greater potential to cause viremia with associated systemic
tion of neurons, the only region of the genome to be tran- flulike symptoms.
scribed generates the latency-associated transcripts
(LATs). These RNAs are not translated into protein but HSV can cause lytic infections of most cells and latent
encode micro-RNAs that inhibit expression of important infection of neurons. Cytolysis generally results from the
immediate early and other genes. virus-induced inhibition of cellular macromolecular syn-
thesis, the degradation of host cell DNA, membrane per-
The early proteins include the DNA-dependent DNA meation, cytoskeletal disruption, and senescence of the
polymerase and a thymidine kinase. As catalytic proteins, cell. Visible changes in the nuclear structure and margin-
relatively few copies of these enzymes are required to ation of the chromatin occur, and Cowdry type A aci-
dophilic intranuclear inclusion bodies are produced.

432 SECTION 5  •  Virology BOX 43.3  Triggers of Herpes Simplex Virus
Recurrences
BOX 43.2  Disease Mechanisms for Herpes
Simplex Viruses Ultraviolet B radiation (skiing, tanning)
Fever (hence the name “fever blister”)
Disease is initiated by direct contact and depends on infected tis- Emotional stress (e.g., final examinations, big date)
sue (e.g., oral, genital, brain). Physical stress (irritation)
Menstruation
Virus causes direct cytopathologic effects. Foods: spicy, acidic, allergies
Virus avoids antibody by cell-to-cell spread and syncytia. Immunosuppression:
Virus establishes latency in neurons (hides from immune r­ esponse).
Virus is reactivated from latency by stress, ultraviolet B light, or Transient (stress related)
Chemotherapy, radiotherapy
immune suppression. Human immunodeficiency virus
Cell-mediated immunity is required for resolution, with a limited

role for antibody.
Cell-mediated immunopathologic effects contribute to s­ ymptoms.

Many strains of HSV also initiate syncytia formation. individual nerve cell within the bundle and allow the virus
In tissue culture, HSV rapidly kills cells, causing them to to travel back down the nerve to cause lesions to develop
appear rounded. at the same dermatome and location each time. The stress
triggers reactivation by promoting replication of the virus
HSV initiates infection through mucosal membranes or in the nerve, by transiently depressing cell-mediated immu-
breaks in the skin. The virus replicates in the cells at the nity, or by inducing both processes. The virus can be reacti-
base of the lesion and infects the innervating neuron, trav- vated despite the presence of antibody. However, recurrent
eling by retrograde transport to the ganglion (the trigemi- infections are generally less severe, more localized, and of
nal ganglia for oral HSV and the sacral ganglia for genital shorter duration than the primary episodes because of the
HSV) (see Fig. 43.5) to establish latent infection. CD8 T nature of the spread and the existence of memory immune
cells and interferon (IFN)-γ are important to maintain responses. 
latency of HSV and other herpesviruses. On reactivation,
the virus then returns to the initial site of infection, and EPIDEMIOLOGY
the infection may be inapparent or may produce vesicular HSV infection is common with more than 700,000 new
lesions. The vesicle fluid contains infectious virions. Tis- HSV-1 and HSV-2 infections in the United States per year.
sue damage is caused by a combination of viral pathology Because HSV can establish latency with the potential for
and immunopathology. The lesion generally heals without asymptomatic recurrence, the infected person is a lifelong
producing a scar. source of contagion (Box 43.4). HSV is transmitted in secre-
tions and by close contact. As an enveloped virus, HSV is
Innate protections, including interferon and natural very labile and is readily inactivated by drying, detergents,
killer (NK) cells, may be sufficient to limit the initial pro- and the conditions of the gastrointestinal tract. Although
gression of the infection. T-helper 1 (TH1)–associated and HSV can infect animal cells, HSV infection is exclusively a
CD8 cytotoxic killer T-cell responses are required to kill infected human disease.
cells and resolve acute disease. The immunopathologic effects
of the cell-mediated and inflammatory responses are also a HSV is transmitted in vesicle fluid, saliva, and vaginal
major cause of the disease signs. Antibody directed against secretions (the “mixing and matching of mucous mem-
the glycoproteins of the virus neutralizes extracellular virus, branes”). The site of infection, and hence the disease, is
limiting its spread, but it is not sufficient to resolve the infec- determined primarily by which mucous membranes are
tion. In the absence of functional cell-mediated immunity, mixed. Both types of HSV can cause oral and genital lesions.
HSV infection is likely to recur and be more severe, and it
may disseminate to the vital organs and the brain. HSV-1 is readily spread by oral contact (kissing) or
through the sharing of drinking glasses, toothbrushes, or
HSV has several ways to escape host protective responses. other saliva-contaminated items. HSV-1 can infect the fin-
The virus blocks the interferon-induced inhibition of viral gers or body through a cut or abraded skin. HSV-1 is also a
protein synthesis and encodes a protein to plug the trans- major cause of genital and pharyngeal herpes. Autoinocu-
porter associated with processing (TAP) channel, prevent- lation may also cause infection of the eyes or fingers.
ing delivery of peptides into the ER, which blocks their
association with class I major histocompatibility complex HSV-2 is spread mainly by sexual contact or autoinoc-
(MHC I) molecules and prevents CD8 T-cell recognition of ulation or from an infected mother to her infant at birth.
infected cells. The virus can escape antibody neutralization Depending on a person’s sexual practices and hygiene,
and clearance by direct cell-to-cell spread and syncytia for- HSV-2 may infect the genitalia, anorectal tissues, or oro-
mation and by going into hiding during latent infection of pharynx. HSV-1 and HSV-2 may cause symptomatic or
the neuron. In addition, the virion and virus-infected cells asymptomatic primary genital infection or recurrences.
express glycoproteins, which are antibody (Fc) (gE/gI) and
complement receptors (gC) that weaken these humoral Neonatal infection usually results from the excretion of
defenses. HSV-2 from the cervix during vaginal delivery (Clinical
Case 43.1) but can occur from an ascending in utero infec-
Latent infection occurs in neurons and results in no tion during a primary infection of the mother or infection
detectable damage. A recurrence can be activated by vari- soon after birth. Neonatal infection results in disseminated
ous stimuli (e.g., stress, trauma, fever, sunlight [ultraviolet and neurologic disease with severe consequences.
B]) (Box 43.3). These events trigger virus replication in an

43  •  Human Herpesviruses 433

BOX 43.4  Epidemiology of Herpes Simplex Clinical Case 43.1  Neonatal Herpes
Virus Simplex Virus

Disease/Viral Factors Parvey and Ch’ien (Pediatrics 65:1150–1153, 1980)
reported a case of neonatal HSV contracted during birth.
Virus causes lifelong infection. During a breech presentation, a fetal monitor was placed
Recurrent disease is a source of contagion. on the buttocks of the baby, and because of the greatly pro-
Virus may cause asymptomatic shedding.  longed labor, the baby was delivered by cesarean section.
The 5-pound boy had minor difficulties that were success-
Transmission fully treated, but on the sixth day, vesicles with an erythe-
matous base appeared at the site in which the fetal monitor
Virus is transmitted in saliva, in vaginal secretions, and by contact had been placed. HSV was grown from the vesicle fluid
with lesion fluid (mixing and matching of mucous membranes). and from spinal fluid, cornea, saliva, and blood. The baby
became moribund, with frequent apneic episodes and sei-
Virus is transmitted orally and sexually and by placement into zures. Intravenous treatment with adenosine arabinoside
eyes and breaks in skin. (Ara-A; vidarabine) was initiated. The baby also developed
bradycardia and occasional vomiting. The vesicles spread
HSV-1 is generally transmitted orally; HSV-2 is generally transmit- to cover the lower extremities and were also on the back,
ted sexually, but not exclusively.  palm, nares, and right eyelid. Within 72 hours of Ara-A
treatment, the baby’s condition started to improve. Treat-
Who Is at Risk? ment was continued for 11 days but discontinued because
of a low platelet count. The baby was discharged on the
Children and sexually active people are at risk for primary disease 45th day after his birthday, and normal development was
of HSV-1 and HSV-2, respectively. reported at 1 and 2 years of age. At 6 weeks after the birth,
a herpes lesion was found on the mother’s vulva. This baby
Physicians, nurses, dentists, and others in contact with oral and was successfully treated with Ara-A and was able to over-
genital secretions are at risk for infections of fingers (herpetic come the damage caused by the infection. The virus, most
whitlow). likely HSV-2, was probably acquired through an abrasion
caused by the fetal monitor while the neonate was in the
Immunocompromised people and neonates are at risk for dis- birth canal. Ara-A has since been replaced with antiviral
seminated life-threatening disease.  drugs that are better, less toxic, and easier to administer,
such as acyclovir, valacyclovir, and famciclovir.
Geography/Season HSV, Herpes simplex virus.

Virus is found worldwide.
There is no seasonal incidence. 

Modes of Control

Antiviral drugs are available for treatment and prophylaxis.
No vaccine is available.
Health care workers should wear gloves to prevent herpetic

whitlow.
People with active genital lesions should refrain from intercourse

until lesions are completely reepithelialized.

Initial infection with HSV-2 occurs later in life than infec- Infected people may experience recurrent mucocutane-
tion with HSV-1 and correlates with increased sexual activ- ous HSV infection (cold sores, fever blisters) (Fig. 43.6)
ity. The current statistics indicate that 20% of adults in the even though they never had a clinically apparent primary
United States are infected with HSV-2, which amounts to infection. The lesions usually occur at the corners of the
approximately 65 million people.  mouth or next to the lips. Recurrent facial herpes infections
are generally reactivated from the trigeminal ganglia. As
CLINICAL SYNDROMES noted earlier, the symptoms of a recurrent episode are less
HSV-1 and HSV-2 are common human pathogens that can severe, more localized, and of shorter duration than those
cause painful, but usually benign, lesions and recurrent dis- of a primary episode. Herpes pharyngitis is becoming a
ease (Fig. 43.3). The same diseases may be caused by either prevalent diagnosis in young adults with sore throats.
HSV-1 or HSV-2, unless noted. HSV can cause significant
morbidity and mortality on infection of the eye or brain and on Herpetic keratitis is almost always limited to one eye. It
disseminated infection of an immunosuppressed person or a neo- can cause recurrent disease, leading to permanent scarring,
nate. In the classic manifestation, the lesion is a clear ves- corneal damage, and blindness. TH17 immune responses
icle on an erythematous base (“dewdrop on a rose petal”) are important for control but contribute to the pathogenesis
and then progresses to pustular lesions, ulcers, and crusted of eye infections.
lesions (Fig. 43.4).
Herpetic whitlow is an infection of the finger, and her-
The lesions of oral herpes, herpes labialis or gingivosto- pes gladiatorum is an infection of the body. The virus estab-
matitis, begin as clear vesicles that rapidly ulcerate. The lishes infection through cuts or abrasions in the skin. Herpetic
vesicles are usually at the crimson border of the lips but may whitlow often occurs in nurses or physicians who attend
be widely distributed around or throughout the mouth, patients with HSV infections, in thumb-sucking children (Fig.
involving the palate, pharynx, gingivae, buccal mucosa, 43.7), and in people who have genital HSV infections. Herpes
and tongue (Fig. 43.5). Many other conditions (e.g., cox- gladiatorum is often acquired during wrestling or rugby.
sackievirus lesions, canker sores, acne) may resemble HSV
lesions. Eczema herpeticum is acquired by children with active
eczema. The underlying disease promotes the spread of
the infection along the skin and potentially to the adrenal
glands, liver, and other organs.

434 SECTION 5  •  Virology

Herpes simplex virus

HSV-1 HSV-2
Meningitis
Encephalitis Encephalitis

Keratoconjunctivitis Oral
Pharyngitis
Oral
Gingivostomatitis A
Tonsillitis
Labialis

Pharyngitis
Esophagitis
Tracheobronchitis
Gladiatorum

Genital Genital Site of viral latency:
Whitlow Perianal trigeminal ganglia

Whitlow
Neonatal HSV

Fig. 43.3  Disease syndromes of herpes simplex virus (HSV). HSV-1 and Transport along Site of active lesion:
HSV-2 can infect the same tissues and cause similar diseases but have a peripheral sensory virus replication in
predilection for the sites and diseases indicated. nerves the epithelium

B

Virus shedding Fig. 43.5  (A) Primary herpes gingivostomatitis. (B) Herpes simplex
virus establishes latent infection and can recur from the trigeminal
ganglia. (A, From Hart, C.A., Broadhead, R.L., 1992. A Color Atlas of Pedi-
atric Infectious Diseases. Wolfe, London, UK. B, Modified from Straus, S.E.,
1993. Herpes simplex virus and its relatives. In: Schaechter, M., Eisenstein,
B.I., Medoff, G. (Eds.), Mechanisms of Microbial Disease, second ed. Williams
& Wilkins, Baltimore, MD.)

PRIMARY

Local symptoms
Pain, itching, dysuria

Sexual Malaise, fever, headache
contact Systemic symptoms Healing

Lesions

Incubation Vesicle Wet ulcer Crust

Tender lymph nodes

Days ؊5 Systemic symptoms 15 20 25
0 5 10
Prodrome

RECURRENCE Lesions
Virus shedding Healing

Local symptoms Fig. 43.6  Cold sore of recurrent herpes labialis. It is less severe than
that of primary disease. (From Hart, C.A., Broadhead, R.L., 1992. A Color
Fig. 43.4  Clinical course of genital herpes infection. The time course Atlas of Pediatric Infectious Diseases. Wolfe, London, UK.)
and symptoms of primary and recurrent genital infection with herpes
simplex virus type 2 are compared. Top, Primary infection; bottom,
recurrent disease. (Data from Corey, L., Adams, H.G., Brown, Z.A., et al.,
1983. Genital herpes simplex virus infection: clinical manifestations, course
and complications. Ann. Intern. Med. 98, 958–972.)

43  •  Human Herpesviruses 435

TABLE 43.2  Laboratory Diagnosis of Herpes Simplex
Virus Infections

Approach Test/Comment

Direct microscopic examina- Multinucleated giant cells and
tion of cells from base of Cowdry type A inclusion bodies
lesion (Tzanck smear) in cells

Cell culture Identifiable cytopathologic effect
in most cell cultures
Assay of tissue biopsy, smear,
cerebrospinal fluid, or Enzyme immunoassay, immuno-
vesicular fluid for HSV fluorescent stain, in situ DNA
antigen or genome probe analysis, or PCRa

HSV type distinction (HSV-1 Type-specific antibody, DNA
versus HSV-2) probe analysis, and PCR

Serology Serology is not useful except for
epidemiology

HSV, Herpes simplex virus; PCR, polymerase chain reaction.
acurrently favored approaches currently favored approaches

Fig. 43.7  Herpetic whitlow. (From Emond, R.T.D., Rowland, H.A.K., 1995. infant through the vaginal canal (possibly at the baby’s
A Color Atlas of Infectious Diseases, third ed. Mosby, London, UK.) scalp-monitor site) because the mother is shedding herpes-
virus at the time of delivery, or it is acquired postnatally
Genital herpes can be caused by HSV-1 or HSV-2. In from family members or hospital personnel. The baby ini-
male patients, the lesions typically develop on the glans or tially appears septic, and vesicular lesions may or may not
shaft of the penis and occasionally in the urethra. In female be present. Because the cell-mediated immune response is
patients, the lesions may be seen on the vulva, vagina, cer- not yet developed in the neonate, HSV disseminates to the
vix, perianal area, or inner thigh and are frequently accom- liver, lung, and other organs, as well as to the central ner-
panied by itching and a mucoid vaginal discharge. Anal sex vous system (CNS). Progression of the infection to the CNS
can lead to HSV proctitis, which is a condition in which the results in death, mental retardation, or neurologic disabil-
lesions are found in the lower rectum and anus. The lesions ity, even with treatment. 
are usually painful. In patients of both sexes, a primary
infection may be accompanied by fever, malaise, and myal- LABORATORY DIAGNOSIS
gia, which are symptoms related to a transient viremia. The Direct Analysis of a Clinical Sample
symptoms and time course of primary and recurrent genital Characteristic cytopathologic effects (CPEs) can be identi-
herpes are compared in Fig. 43.4. fied in a Tzanck smear (a scraping of the base of a lesion),
Papanicolaou (Pap) smear, or biopsy specimen (Table
Recurrent HSV disease is shorter in duration and less 43.2). CPEs include syncytia, “ballooning” cytoplasm, and
severe than the primary episode. In approximately 50% of Cowdry type A intranuclear inclusions (see Fig. 39.2). A
patients, recurrences are preceded by a characteristic pro- definitive diagnosis can be made by demonstrating viral
drome of burning or tingling in the area in which the lesions antigen (using immunofluorescence or the immunoperoxi-
eventually erupt. Episodes of recurrence may be as frequent dase method) or DNA (using in situ hybridization or PCR) in
as every 2 to 3 weeks or may be infrequent. Unfortunately, the tissue sample or vesicle fluid. 
any infected person may shed the virus asymptomatically. Virus Isolation
Such individuals are important vectors for spread of this Virus isolation allows archiving and additional testing.
virus. Virus can be obtained from vesicles but not crusted lesions.
Specimens are collected by aspiration of the lesion fluid or
Herpes encephalitis is usually caused by HSV-1. The by application of a cotton swab to the vesicles and kept cold
lesions are generally limited to one of the temporal lobes. but not frozen at −20° C. The sample is inoculated directly
The viral pathology and immunopathology cause destruc- into cell cultures.
tion of the temporal lobe and give rise to erythrocytes in the
cerebrospinal fluid, seizures, focal neurologic abnormali- HSV produces CPEs within 1 to 3 days in HeLa cells,
ties, and other characteristics of viral encephalitis. HSV is human embryonic fibroblasts, and other cells. Infected cells
the most common viral cause of sporadic encephalitis become enlarged and rounded (see Fig. 39.4). Some isolates
and results in significant morbidity and mortality, even in induce fusion of neighboring cells, giving rise to multinucle-
patients who receive appropriate treatment. Unlike arbovi- ated giant cells (syncytia). A sensitive approach for iden-
rus encephalitis, the disease occurs at all ages and at any tification uses a cell line that expresses β-galactosidase on
time of the year. HSV meningitis may be a complication of HSV infection of cells (enzyme-linked viral-inducible system
genital HSV-2 infection, and if so, symptoms often resolve [ELVIS]). Addition of the appropriate substrate produces
by themselves. color and allows detection of the enzyme in the infected cells. 

HSV infection in the neonate is a devastating and
often fatal disease. It may be acquired in utero, but more
commonly, it is contracted either during passage of the

436 SECTION 5  •  Virology BOX 43.5  U.S. Food and Drug
Administration–Approved Antiviral
Genome Detection Treatments for Herpesvirus Infections
HSV type-specific DNA probes, specific DNA primers for
PCR, and quantitative PCR are used to detect and differenti- Herpes Simplex 1 and 2
ate HSV-1 and HSV-2. PCR analysis of the clinical sample
or infected tissue culture media has become the method of Acyclovir
choice for detection and distinction of HSV-1 and HSV-2 for Penciclovir
most patients.  Valacyclovir
Serology Famciclovir
Serologic procedures are useful only for diagnosing a pri- Trifluridine 
mary HSV infection and for epidemiologic studies. They are Varicella-Zoster Virus
not useful for diagnosing recurrent disease because a sig-
nificant rise in antibody titers does not usually accompany Acyclovir
recurrent disease.  Famciclovir
Valacyclovir
TREATMENT, PREVENTION, AND CONTROL Varicella-zoster immune globulin
HSV encodes several target enzymes for antiviral drugs Zoster immune plasma
(Box 43.5) (see Chapter 40). Most antiherpes drugs are Live or adjuvanted subunit vaccine 
nucleoside analogs that are activated by the viral thymidine Epstein-Barr Virus
kinase and inhibit the viral DNA polymerase, which is an
enzyme essential for viral replication and the best antiviral None 
drug target. Treatment prevents or shortens the course of Cytomegalovirus
primary or recurrent disease. None of the drug treatments Ganciclovira
can eliminate latent infection. Valganciclovira
Foscarneta
The prototype anti-HSV drug is acyclovir (ACV). Vala- Cidofovira
cyclovir (the valyl ester of ACV), penciclovir, and fam-
ciclovir (a derivative of penciclovir) are related to ACV in aAlso inhibits herpes simplex and varicella-zoster viruses.
their mechanisms of action but have different pharmaco-
logic properties (see Fig. 40.1). syncytia formation. Docosanol inhibits entry of the virus,
and other nonprescription treatments may be effective for
Phosphorylation of ACV and penciclovir by the viral specific individuals.
thymidine kinase and cellular enzymes activates the
drug as a substrate for the viral DNA polymerase. These Avoidance of direct contact with lesions reduces the risk
drugs are then incorporated into and prevent elonga- of infection. Unfortunately, the symptoms may be inappar-
tion of the viral DNA (see Fig. 40.2). ACV, valacyclovir, ent; thus the virus can be transmitted unknowingly. Physi-
penciclovir, and famciclovir are relatively nontoxic, effec- cians, nurses, dentists, and technicians must be especially
tive in treating serious presentations of HSV disease and careful when handling potentially infected tissue or fluids.
first episodes of genital herpes, and are also used for pro- Wearing gloves can prevent acquisition of infections of the
phylactic treatment. fingers (herpetic whitlow). People with recurrent herpetic
whitlow disease are very contagious and can spread the
The most prevalent form of resistance to these drugs infection to patients.
results from mutations that inactivate the thymidine kinase,
preventing conversion of the drug to its active form. Muta- HSV is readily inactivated by soap, disinfectants, bleach,
tion of the viral DNA polymerase also produces resistance. and 70% ethanol. Washing with soap readily disinfects the
Fortunately, resistant strains appear to be less virulent. virus.

ACV and its analogs are effective against all HSV infec- Patients who have a history of genital HSV infection must
tions, including encephalitis, disseminated herpes, and be instructed to refrain from sexual intercourse while they
other serious herpes diseases. The fact that it is not toxic to have prodromal symptoms or lesions and to resume sexual
uninfected cells allows use of it and its analogs as a suppres- intercourse only after lesions are completely reepithelialized
sive treatment to prevent recurrent outbreaks, especially because the virus may be transmitted from lesions that have
in immunosuppressed people. A recurrent episode may be crusted over. Condoms may be useful and are undoubtedly
prevented if it is treated before or soon after the triggering better than nothing but may not be fully protective.
event. The replication of HSV can be inhibited, but treat-
ment cannot resolve the latent HSV infection. A pregnant woman who has active genital HSV infec-
tion or who is asymptomatically shedding the virus in the
Although cidofovir and adefovir are active against vagina at term may transmit HSV to the neonate if the
HSV, cidofovir is only approved for treatment of CMV. infant is delivered vaginally. Such transmission can be pre-
Vidarabine (adenosine arabinoside [Ara A]) is less solu- vented by cesarean section.
ble, less potent, and more toxic than ACV and is no longer
in use. Trifluridine, penciclovir, and ACV have replaced No vaccine is currently available for HSV. However,
iododeoxyuridine as topical agents for the treatment of killed, subunit, vaccinia hybrid, genetically attenuated, and
herpetic keratitis. Tromantadine, an amantadine deriva- DNA vaccines are being developed to prevent acquisition of
tive, is approved for topical use in countries other than the virus or to treat infected people. The glycoprotein D is
the United States. It works by inhibiting penetration and being used in several of these experimental vaccines. 

43  •  Human Herpesviruses 437

Varicella-Zoster Virus lymphatic system to the cells of the reticuloendothelial sys-
tem (Figs. 43.8 and 43.9; Box 43.6). A secondary viremia
VZV causes chickenpox (varicella) and, on recurrence, then occurs and spreads the virus throughout the body and
causes herpes zoster, or shingles. As an alphaherpesvirus, to the skin. The virus infects T cells, and these cells can home
VZV shares many characteristics with HSV, including (1) to the skin and transfer virus to skin epithelial cells. The virus
the ability to establish latent infection of neurons and recur- overcomes inhibition by IFN-α, and vesicles are produced in
rent disease, (2) the importance of cell-mediated immunity the skin. The virus remains cell associated and is transmitted
in controlling and preventing serious disease, and (3) the by cell-to-cell interaction, except for terminally differentiated
characteristic blister-like lesions. Like HSV, VZV encodes a epithelial cells in the lungs and keratinocytes of skin lesions,
thymidine kinase and is susceptible to the same antivi- which can release infectious virus. Virus replication in the
ral drugs. Unlike HSV, VZV spreads predominantly by the lung is a major source of contagion. The virus causes a der-
respiratory route and, after local replication of the virus mal vesiculopustular rash that develops over time in succes-
in the respiratory tract, by viremia to form skin lesions over sive crops. Fever and systemic symptoms occur with the rash.
the entire body.
The virus becomes latent in the dorsal root, cranial nerve,
STRUCTURE AND REPLICATION and other ganglia after the primary infection. The virus can
VZV has the smallest genome of the HHVs. VZV replicates be reactivated in older adults when immunity wanes or in
in a similar manner but slower and in fewer types of cells patients with impaired cellular immunity. On reactivation,
than HSV. Human diploid fibroblasts in vitro and activated the virus replicates and is released along the length of the
T cells, epithelial cells, and epidermal cells in  vivo sup- neuron to infect the skin, causing a vesicular rash along the
port productive VZV replication. Newly synthesized VZV entire dermatome, which is known as herpes zoster, or
is sequestered into lysosomes and degraded in most cells shingles. This damages the neuron and may result in very
because of its binding to the mannose-6-phosphate receptor painful postherpetic neuralgia.
but is released from terminally differentiated skin cells that
lack this protein. As such, it spreads within the body by cell– Viral replication Viral replication
cell contact. Like HSV, VZV establishes a latent infection of in regional in liver, spleen,
neurons, but unlike HSV, several viral RNAs and specific lymph nodes other organs
viral proteins can be detected in the latently infected cells.  Infection of Infection of
mucosa of upper skin and
PATHOGENESIS AND IMMUNITY respiratory tract Primary Secondary appearance of
VZV-infected cells show similar CPE to those seen in HSV- viremia viremia vesicular rash
infected cells with Cowdry type A intranuclear inclusions
and syncytia. Fever

VZV is generally acquired by inhalation, and primary Days
infection begins in the tonsils and mucosa of the respira-
tory tract. The virus progresses via the bloodstream and 0 5 10 15 20

Incubation period Contagious
period

Fig. 43.9  Time course of varicella (chickenpox). The course in young
children, as presented in this figure, is generally shorter and less severe
than that in adults.

Droplets Respiratory Lymphatics Liver, spleen,
tract reticuloendothelial
system, T cells
Viremia BOX 43.6  Disease Mechanisms of Varicella-
Fever, Zoster Virus
malaise,
headache Initial replication is in the respiratory tract.
Infects epithelial cells, fibroblasts, T cells, and neurons.
Vesicle progression Mucous Can form syncytia and spread directly from cell to cell.
Macules Papules Vesicles Skin membrane Spread by viremia in T cells to skin and causes lesions in succes-

Pustules Crusts sive crops.
Life-threatening pneumonia occurs in adults with primary infec-
Latency
in neuron tion caused by vigorous inflammatory response.
Can evade antibody clearance, and cell-mediated immune re-
Fig. 43.8  Mechanism of spread of varicella-zoster virus (VZV) within
the body. VZV initially infects the respiratory tract and is spread to the sponse is essential to control infection.
reticuloendothelial system and T cells and then by cell-associated vire- Disseminated life-threatening disease can occur in immunocom-
mia to the skin.
promised people.
Establishes latent infection of neurons, usually dorsal root and

cranial nerve ganglia.
Herpes zoster is a recurrent disease; it results from virus replica-

tion along the entire dermatome.
Herpes zoster results from depression of cell-mediated immunity.

VZV, Varicella-zoster viurs.

438 SECTION 5  •  Virology

IFN-α, interferon-stimulated protections, and NK and T of a patient’s latent virus. The disease develops in approxi-
cells limit the spread of the virus in tissue, but antibody is mately 10% to 20% of the population infected with VZV,
important for limiting the viremic spread of VZV. Passive and the incidence rises with age. Herpes zoster lesions con-
immunization with varicella-zoster immunoglobulin tain viable virus and therefore may be a source of varicella
(VZIg) within 4 days of exposure is protective. Cell-medi- infection in a nonimmune person (i.e., a child). 
ated immunity is essential for resolving the acute disease CLINICAL SYNDROMES
and controlling the latent infection. The virus causes more Varicella (chickenpox) is one of the five classic child-
disseminated and more serious disease in the absence of hood exanthems (along with rubella, roseola, fifth dis-
cell-mediated immunity (e.g., in children with leukemia) ease, and measles). The disease results from a primary
and may recur on immunosuppression. Although impor- infection with VZV; it is usually a mild disease of childhood
tant for protection, cell-mediated immune responses con- and is normally symptomatic, although asymptomatic
tribute to the symptomatology. An overzealous response in infection can occur (see Fig. 43.9). Varicella characteris-
adults is responsible for causing more extensive cell dam- tics include fever and a maculopapular rash that appear
age and a more severe manifestation (especially in the lung) after an incubation period of approximately 14 days (Fig.
in primary infection than that seen in children. T-cell and 43.10). Within hours, each maculopapular lesion forms a
antibody levels decrease later in life, allowing VZV recur- thin-walled vesicle on an erythematous base (“dewdrop on
rence and herpes zoster disease.  a rose petal”) that measures approximately 2 to 4 mm in
diameter. This vesicle is the hallmark of varicella. Within
EPIDEMIOLOGY 12 hours, the vesicle becomes pustular and begins to crust,
after which scabbed lesions appear. Successive crops of
VZV is extremely communicable, with rates of infection lesions appear for 3 to 5 days, and at any given time, all
exceeding 90% among susceptible household contacts (Box stages of skin lesions can be observed.
43.7). The disease is spread principally by the respiratory
route but may also be spread through contact with skin ves- The rash spreads across the entire body but is more preva-
icles. Patients are contagious before and during symptoms. lent on the trunk and head than on the extremities. Its pres-
More than 90% of adults in developed countries have the ence on the scalp distinguishes it from many other rashes. The
VZV antibody. Herpes zoster results from the reactivation lesions itch and cause scratching, which may lead to bacterial
superinfection and scarring. Lesions on the mucous mem-
BOX 43.7  Epidemiology of Varicella-Zoster brane typically occur in the mouth, conjunctivae, and vagina.
Virus
Primary infection is usually more severe in adults than
Disease/Viral Factors in children. Interstitial pneumonia may occur in 20%
to 30% of adult patients and may be fatal. The pneumonia
Causes lifelong infection. results from inflammatory reactions at this primary site of
Recurrent disease is a source of contagion.  infection.

Transmission As noted earlier, herpes zoster (zoster means “belt”
or “girdle”) is a recurrence of a latent varicella infection
Virus is transmitted mainly by respiratory droplets but also by acquired earlier in the patient’s life. Severe pain in the area
direct contact.  innervated by the nerve usually precedes the appearance of
the chickenpox-like lesions. The rash is limited to a derma-
Who Is at Risk? tome and resembles varicella (Fig. 43.11). Common sites of

Children (aged 5 to 9 years) experience mild classic disease. Fig. 43.10  Characteristic rash of varicella in all stages of its evolution.
Teenagers and adults are at risk for more severe disease with (From Hart, C.A., Broadhead, R.L., 1992. A Color Atlas of Pediatric Infectious
Diseases. Wolfe, London, UK.)
potential pneumonia.
Immunocompromised people and newborns are at risk for

life-threatening pneumonia, encephalitis, and progressive dis-
seminated varicella.
Elderly and immunocompromised people are at risk for recurrent
disease (herpes zoster [shingles]) caused by a waning immune
response. 

Geography/Season

Virus is found worldwide.
There is no seasonal incidence. 

Modes of Control

Antiviral drugs are available.
Varicella-zoster immunoglobulin is available for immunocompro-

mised people and staff exposed to virus, as well as newborns of
mothers showing symptoms within 5 days of birth.
Live vaccine (Oka strain) is available for children (varicella) and
adults (zoster). Adjuvanted subunit vaccine also is available
for zoster.

43  •  Human Herpesviruses 439

Fig. 43.11  Herpes zoster (“shingles”) in a thoracic dermatome. generally mild and induces lifelong immunity, exposure of
children to VZV early in life is often encouraged. However,
presentation are a quadrant of the head or along a thoracic high-risk people (e.g., immunosuppressed children) should
dermatome. A chronic pain syndrome called postherpetic be protected from exposure to VZV.
neuralgia, which can persist for months to years, occurs in
as many as 30% of patients in whom herpes zoster develops. Immunocompromised patients susceptible to severe dis-
ease may be protected from serious disease through the
VZV infection in immunocompromised patients or neo- administration of VZIg. VZIg is prepared through the pool-
nates can result in serious, progressive, and potentially fatal ing of plasma from seropositive people. VZIg prophylaxis
disease. Defects of cell-mediated immunity in such patients can prevent viremic spread leading to disease but is ineffec-
increase the risk for dissemination of the virus to the lungs, tive as a therapy for patients already suffering from active
brain, and liver, which may be fatal. The disease may occur varicella or herpes zoster disease.
in response to a primary exposure to varicella or because of
recurrent disease.  A live attenuated vaccine for VZV (Oka strain)
(Varivax) has been licensed for use in the United States and
LABORATORY DIAGNOSIS elsewhere and is administered after 1 year of age on the
Isolation of VZV is not routinely done because the virus is same schedule as the measles, mumps, and rubella vaccine.
labile during transport to the laboratory and replicates The vaccine induces production of protective antibody and
poorly in vitro. PCR and genome detection techniques are cell-mediated immunity. A stronger version of this vaccine
especially useful for confirming a diagnosis. A direct fluores- (Zostavax) is available for adults older than 60 years; it
cent antibody to membrane antigen (FAMA) test can also be boosts antiviral responses to limit the onset of zoster. A sub-
used to examine skin lesion scrapings or biopsy specimens. unit vaccine (Shingrix) consisting of the VZV glycoprotein E
and an adjuvant is given in two doses and is also available. 
Serologic tests that detect antibodies to VZV are used to
screen populations for immunity to VZV. However, anti- Epstein-Barr Virus
body levels are normally low, so sensitive tests such as
immunofluorescence and enzyme-linked immunosorbent EBV is the ultimate B-lymphocyte parasite, and the diseases
assay (ELISA) must be performed to detect the antibody. it causes reflect this association. EBV was discovered by
A significant increase in antibody level can be detected in electron-microscopic observation of characteristic herpes
people experiencing herpes zoster.  virions in biopsy specimens of a B-cell neoplasm, African
Burkitt lymphoma (AfBL). Its association with infectious
TREATMENT, PREVENTION, AND CONTROL mononucleosis was discovered accidentally when serum
Treatment may be appropriate for adults and immunocom- collected from a laboratory technician convalescing from
promised patients with VZV infections and for people with infectious mononucleosis was found to contain the antibody
zoster, but no treatment is usually necessary for children that recognized AfBL cells. This finding was later confirmed
with varicella. ACV, famciclovir, and valacyclovir have in a large serologic study performed on college students.
been approved for the treatment of VZV infections. The VZV
DNA polymerase is much less sensitive to ACV treatment EBV causes heterophile antibody–positive infectious mono-
than the HSV enzyme, requiring larger doses of ACV or the nucleosis and stimulates the growth and immortalizes B cells in
improved pharmacodynamics of famciclovir and valacyclo- tissue culture. EBV has been causally associated with AfBL
vir (see Box 43.5). There is no good treatment, but analge- (endemic Burkitt lymphoma), Hodgkin disease, and
sics and other painkillers, topical anesthetics, or capsaicin nasopharyngeal carcinoma. EBV has also been associ-
cream may provide some relief from the postherpetic neu- ated with B-cell lymphomas in patients with acquired or
ralgia that follows zoster. congenital immunodeficiencies.

As with other respiratory viruses, it is difficult to limit the STRUCTURE AND REPLICATION
transmission of VZV. Because VZV infection in children is EBV is a member of the subfamily Gammaherpesviri-
nae, with a very limited host range and a tissue tropism
defined by the limited cellular expression of its receptor. The
primary receptor for EBV is also the receptor for the C3d com-
ponent of the complement system (also called CR2 or CD21). It
is expressed on B cells of humans and New World monkeys
and on some epithelial cells of the oropharynx and naso-
pharynx. EBV also binds to MHC II.

EBV infection has the following three potential outcomes,
it can
1 . Replicate in B cells or epithelial cells permissive for EBV

replication and produce virus,
2 . Cause latent infection of memory B cells in the presence

of competent T cells, and
3 . Stimulate growth and immortalize B cells.

EBV encodes more than 70 proteins, different groups of
which are expressed for the different types of infections.

440 SECTION 5  •  Virology

TABLE 43.3  Markers of Epstein-Barr Virus Infection

Name Abbreviation Characteristics Biological Association Clinical Association
Anti-EBNA develops after
EBV nuclear antigens EBNAs Nuclear EBNAs are nonstructural antigens
and first antigens to appear; resolution of infection
Early antigen EA-R Only cytoplasmic EBNAs seen in all infected and
transformed cells —
EA-D Diffuse in cytoplasm and
nucleus EA-R appears before EA-D; appear- Anti–EA-D seen in infectious
Viral capsid antigen VCA ance is first sign that infected cell mononucleosis
Cytoplasmic has entered lytic cycle
Membrane antigen MA Anti-VCA IgM is transient;
Heterophile antibody — Cell surface — anti-VCA IgG is persistent
Recognition of Paul-Bunnell
VCA are late proteins; found in virus- Same as VCA
antigen on sheep, horse, or producing cells Early symptom occurs in
bovine erythrocytes
MAs are envelope glycoproteins more than 50% of patients

EBV-induced B-cell proliferation pro-
motes production of heterophile
antibody

EA, Early antigen; EBNA, Epstein-Barr nuclear antigen; EBV, Epstein-Barr virus; Ig, immunoglobulin; MA, membrane antigen; VCA, viral capsid antigen.

EBV in saliva infects epithelial cells and then naive PATHOGENESIS AND IMMUNITY
resting B cells in the tonsils. The growth of the B cells is EBV has adapted to the human B cell and manipulates and
stimulated first by virus binding to the C3d receptor, a uses the different phases of B-cell development to establish
B-cell growth-stimulating receptor, and then by expres- a lifelong infection. The diseases of EBV result from either
sion of the transformation and latency proteins. These an overactive immune response (infectious mononucleosis)
include Epstein-Barr nuclear antigens (EBNAs) 1, 2, or the lack of effective immune control (lymphoproliferative
3A, 3B, and 3C; latent proteins (LPs); latent membrane disease and hairy cell leukoplakia).
proteins (LMPs) 1 and 2; and two small Epstein-Barr–
encoded RNA (EBER) molecules, EBER-1 and EBER-2. The productive infection of B cells and epithelial cells of
The EBNAs and LPs are DNA-binding proteins that are the oropharynx, such as in the tonsils (Fig. 43.12 and Box
essential for establishing and maintaining the infection 43.8), promotes virus shedding into saliva to transmit the
(EBNA-1), immortalization (EBNA-2), and other pur- virus to other hosts and establishes a viremia to spread the
poses. The LMPs are membrane proteins with oncopro- virus to other B cells in lymphatic tissue and blood.
tein-like activity. The genome becomes circularized; the
cells proceed to follicles that become germinal centers in EBV proteins replace host factors that normally activate
the lymph node, in which the infected cells differentiate B-cell growth and development. In the absence of T cells
into memory cells. EBV protein synthesis ceases, and the (e.g., in tissue culture), EBV can immortalize B cells and
virus establishes latency in these memory B cells. EBNA-1 promote the development of B-lymphoblastoid cell lines.
is present at cell division to hold onto and retain the In  vivo, B-cell activation and proliferation occurs and is
genome in the cells. indicated by the spurious production of an IgM antibody to
the Paul-Bunnell antigen, termed the heterophile anti-
Antigen stimulation of the B cells and infection of certain body (see later discussion of serology).
epithelial cells allow transcription and translation of the
ZEBRA (peptide encoded by the Z-gene region) transcrip- The outgrowth of the B cell is controlled by a normal
tional activator protein, which activates the immediate T-cell response to B-cell proliferation and to EBV antigenic
early genes of the virus and the lytic cycle. After synthesis peptides. B cells are excellent antigen-presenting cells and
of the DNA polymerase and replication of DNA, the struc- present EBV antigens on both MHC I and MHC II molecules.
tural and other late proteins are synthesized. They include The activated T cells appear as atypical lymphocytes (also
gp350/220 (related glycoproteins of 350,000 and 220,000 called Downey cells) (Fig. 43.13). They increase in num-
Da), which is the viral attachment protein, and other gly- ber in the peripheral blood during the second week of infec-
coproteins. These glycoproteins bind to CD21 and MHC II tion, accounting for 10% to 80% of the total white blood cell
molecules, receptors on B cells and epithelial cells, and pro- count at this time (hence the “mononucleosis”).
mote fusion of the envelope with cell membranes.
Infectious mononucleosis is essentially a “civil war”
The viral proteins produced during a productive infec- between the EBV-infected B cells and the protective T cells. The
tion are serologically defined and grouped as early antigen classic lymphocytosis (increase in mononuclear cells),
(EA), viral capsid antigen (VCA), and the glycoproteins swelling of lymphoid organs (lymph nodes, spleen, and
of the membrane antigen (MA) (Table 43.3). An early liver), and malaise associated with infectious mononucleo-
protein mimics a cellular inhibitor of apoptosis, and a late sis results mainly from the activation and proliferation of
protein mimics the activity of human interleukin (IL)-10 T cells. A large amount of energy is required to power the
(BCRF-1), which enhances B-cell growth and inhibits TH1 T-cell response, leading to great fatigue. The sore throat of
immune responses.  infectious mononucleosis is a response to EBV-infected epi-
thelium and B cells in the tonsils and throat. Children have

43  •  Human Herpesviruses 441

B cell Proliferation EBNAs 1, 2, 3AXi,md-liimsnekNuaenosdoeTprcoellilfserativeLlyemupkheommiaa/

Saliva Epithelial cell LP 3B, 3C
sharing EBER 1, 2

LMPs 1, 2A, 2B

Lytic MONONUCLEOSIS CD8 T cells
cycle (Atypical lymphocytes)
(60%-70% of total WBCs)

EA ZEBRA EBNA-1 Cofactors African Burkitt
EBNA VCA Memory lymphoma
B cell
MA
VIRUS

Latency

Fig. 43.12  Progression of Epstein-Barr virus (EBV) infection. Infection may result in lytic, latent, or immortalizing infection, which can be distinguished
on the basis of production of virus and expression of different viral proteins and antigens. T cells limit the outgrowth of the EBV-infected cells and main-
tain the latent infection. CD, Cluster of differentiation; EA, early antigen; EBER, Epstein-Barr–encoded RNA; EBNA, Epstein-Barr nuclear antigen; LMPs,
latent membrane proteins; LP, latent protein; MA, membrane antigen; VCA, viral capsid antigen; WBCs, white blood cells; ZEBRA, peptide encoded by
the Z gene region.

BOX 43.8  Disease Mechanisms of Epstein- Fig. 43.13  Atypical T-cell (Downey cell) characteristic of infectious
Barr Virus mononucleosis. The cells have a more basophilic and vacuolated cyto-
plasm than normal lymphocytes, and the nucleus may be oval, kidney
Virus in saliva initiates infection of oral epithelia and tonsillar B shaped, or lobulated. The cell margin may seem to be indented by
cells. neighboring red blood cells.

There is productive infection of epithelial cells and B cells. EBV may be reactivated when the memory B cell is acti-
Virus promotes growth of B cells (immortalizes). vated (especially in the tonsils or oropharynx) and may be
T cells are stimulated by infected B cells; they kill and limit B-cell shed in saliva. 

outgrowth. T cells are required for controlling infection. EPIDEMIOLOGY
Antibody role is limited. At least 70% of the population of the United States is infected
EBV establishes latency in memory B cells and is reactivated when by age 30. EBV is transmitted in saliva (Box 43.9). More than
90% of EBV-infected people intermittently shed the virus for
the B cell is activated. life, even when totally asymptomatic. Children can acquire
T-cell response (lymphocytosis) contributes to symptoms of infec- the virus at an early age by sharing contaminated drink-
ing glasses. Children generally have subclinical disease. Saliva
tious mononucleosis. sharing between adolescents and young adults often occurs
There is causative association with lymphoma in immunosup- during kissing; thus EBV mononucleosis has earned the
nickname “the kissing disease.” Disease in these people may
pressed people and African children living in malarial regions go unnoticed or may manifest in varying degrees of severity.
(African Burkitt lymphoma) and with nasopharyngeal carci-
noma in China. The geographic distribution of some EBV-associated
EBV-associated B-cell lymphomas may result from immunosup- neoplasms indicates a possible association with cofactors.
pression.

EBV, Epstein-Barr virus.

a less active immune response to EBV infection and there-
fore have mild disease.

During productive infection, antibody is first developed
against the components of the virion, VCA, and MA, and
later against the EA. After resolution of the infection (lysis
of the productively infected cells), antibody against the
nuclear antigens (EBNAs) is produced. T cells are essential
for limiting the proliferation of EBV-infected B cells and con-
trolling the disease (Fig. 43.14). EBV counteracts some of
the protective action of TH1 CD4 T-cell responses during
productive infection by producing an IL-10 analog (BCRF-
1) that inhibits the protective TH1 CD4 T-cell responses and
stimulates B-cell growth.

The virus persists in peripheral blood memory B cells and
in the tonsils. They can be detected in at least one memory
B cell per milliliter of blood for the infected person’s lifetime.

442 SECTION 5  •  Virology

Malaria appears to be a cofactor in the progression of Transplant recipients, patients with the acquired immu-
chronic or latent EBV infection to AfBL. The restriction nodeficiency syndrome (AIDS), and genetically immuno-
of nasopharyngeal carcinoma to people living in certain deficient people are at high risk for lymphoproliferative
regions of China indicates a possible genetic predisposition disorders initiated by EBV. These disorders may appear as
to the cancer or the presence of cofactors in the food or envi- polyclonal and monoclonal B-cell lymphomas. Such people
ronment. More subtle mechanisms may facilitate the role of are also at high risk for a productive EBV infection in the
EBV in 30% to 50% of cases of Hodgkin disease and other form of hairy oral leukoplakia. 
cancers. CLINICAL SYNDROMES
Heterophile Antibody–Positive Infectious
Resolution/Latency Mononucleosis
The triad of classic symptoms for infectious mononucleosis
Lymph is lymphadenopathy (swollen glands), splenomegaly
Liver nodes Spleen (large spleen), and exudative pharyngitis accompanied
by high fever, malaise, and often hepatosplenomegaly
EBV in B cells and B-cell T-cell Swelling (large liver and spleen) (Clinical Case 43.2). A rash may
saliva epithelial proliferation activation occur, especially after ampicillin treatment (for a possible
cells of strep throat). The major complaint of people with infectious
oropharynx mononucleosis is fatigue (Fig. 43.15). The disease is rarely
fatal in healthy people but can cause serious complications
Malaise resulting from neurologic disorders, laryngeal obstruction,
or rupture of the spleen. Neurologic complications include
Shedding Heterophile meningoencephalitis and Guillain-Barré syndrome. Similar
in saliva antibody to infections caused by other herpesviruses, EBV infection
in a child is much milder than infection in an adolescent
Pharyngitis Atypical or adult. In fact, infection in children is usually subclinical.
lymphocytes
(Downey cells) Clinical Case 43.2 Epstein-Barr
Virus in the Immunocompromised
Fig. 43.14  Pathogenesis of Epstein-Barr virus (EBV). EBV is acquired Individual
by close contact between persons through saliva and infects B cells.
Resolution of the EBV infection and many of the symptoms of infec- Purtilo and associates (Ann Intern Med 101:180–186,
tious mononucleosis result from activation of T cells in response to the 1984) reported on a boy with Duncan disease who
infection. presented with reduced levels of IgA, a history of thrush,
and recurrent episodes of otitis media. This member of the
BOX 43.9  Epidemiology of Epstein-Barr Duncan family had an X-linked recessive, progressive,
Virus combined, variable immunodeficiency disease caused by a
mutation in the SH2D1A protein, which prevents proper
Disease/Viral Factors communication between B and T cells. After exposure
to EBV at age 11 years, the boy did not develop antibod-
Virus causes lifelong infection. ies to EBV, but generic serum IgM levels increased, and
Recurrent disease is primary source of contagion. EBNA-positive immortalized B-cell lines readily grew from
Virus may cause asymptomatic shedding.  his peripheral blood. Establishment of the B-cell lines is
indicative of aberrant T-cell control of the virus-induced
Transmission B-cell proliferation. At age 18 years, he was treated with
packed red cells for red cell aplasia; then 9 weeks later he
Transmission occurs via saliva, close oral contact (“kissing dis- developed infectious mononucleosis with fever, generalized
ease”), or sharing of items such as toothbrushes and cups.  lymphadenomegaly, tender liver and swollen spleen, lym-
phocytosis with a predominance of atypical lymphocytes,
Who Is at Risk? and a positive Monospot test. Within another 6 months, he
was agammaglobulinemic with no detectable B cells and
Children experience asymptomatic disease or mild symptoms. suffered from Haemophilus influenzae and Mycobacterium
Teenagers and adults are at risk for infectious mononucleosis. tuberculosis pneumonias. After an additional 5 months, B
Immunocompromised people are at highest risk for life-threaten- cells were again detected. The onset of infectious mono-
nucleosis at age 18 years may have resulted from new
ing neoplastic disease.  infection or a reactivation of the earlier infection. This case
illustrates the unusual nature of EBV and other virus infec-
Geography/Season tions when the immune response is compromised.

Infectious mononucleosis has worldwide distribution. EBNA, Epstein-Barr nuclear antigen; EBV, Epstein-Barr virus;
There is causative association with African Burkitt lymphoma in Ig, immunoglobulin.

the malarial belt of Africa.
There is no seasonal incidence. 

Modes of Control

There are no modes of control.

43  •  Human Herpesviruses 443

Up to 2-month BOX 43.10 Diagnosis of Epstein-Barr Virus
incubation period
1 . Symptoms
Clinical Fever a. Mild headache, fatigue, fever
syndrome Lymphadenopathy/ b. Triad: lymphadenopathy, splenomegaly, exudative phar-
hepatosplenomegaly
Pharyngitis yngitis
c. Other: hepatitis, ampicillin-induced rash
Malaise and fatigue 2. Complete blood cell count
Virus in saliva a. Hyperplasia
b. Atypical lymphocytes (Downey cells, T cells)
Laboratory Atypical lymphocytes 3. Heterophile antibody (transient)
data 4 . EBV–antigen-specific antibody
Heterophile antibody titer 5 . Genome detection by PCR
Time
Days 5 10 15 20 Months1 2 3 4 5 EBV, Epstein-Barr virus; PCR, polymerase chain reaction.
Serologic
data Anti-EA IgG EBV was first associated with AfBL (endemic lym-
Anti-VCA IgM Anti-EBNA phoma) and then Burkitt lymphoma elsewhere in the
world, Hodgkin lymphoma, and several other lymphopro-
Fig. 43.15  Clinical course of infectious mononucleosis and laboratory liferative diseases. AfBL is a poorly differentiated monoclo-
findings of those with the infection. Epstein-Barr virus infection may nal B-cell lymphoma of the jaw and face that is endemic in
be asymptomatic or may produce the symptoms of mononucleosis. children living in the malarial regions of Africa. EBV infec-
The incubation period can last as long as 2 months. EA, Early antigen; tion facilitates the survival of cells that undergo a chromo-
EBNA, Epstein-Barr nuclear antigen; Ig, immunoglobulin; VCA, viral cap- somal translocation that juxtaposes the c-MYC oncogene to
sid antigen. a very active promoter, such as an immunoglobulin gene
promoter [t(8;14), t(8;22), t(8;2)], to allow tumor growth.
Mononucleosis-like syndromes can also be caused by Virions can occasionally be seen on electron micrographs of
CMV, HHV-6, Toxoplasma gondii, and human immunodefi- infected material. The tumor cells are also relatively invis-
ciency virus (HIV). As for EBV, mononucleosis syndrome is ible to immune control. Malaria may enhance the develop-
caused by T-cell proliferation in response to infection of an ment of AfBL by promoting the proliferation of EBV-bearing
antigen-presenting cell; a B cell; a macrophage; or a den- memory B cells.
dritic cell, which stimulates CD4 and CD8 T cells with anti-
genic peptides on MHC II and MHC I. Heterophile antibody EBV is also associated with nasopharyngeal carci-
is not generated during these syndromes.  noma, which is endemic in adults in Asia. The tumor
cells contain EBV DNA, but unlike Burkitt lymphoma, in
Chronic Disease which the tumor cells are derived from lymphocytes, the
EBV can cause cyclic recurrent disease in some people. tumor cells of nasopharyngeal carcinoma are of epithe-
These patients experience chronic tiredness and may also lial origin. 
have low-grade fever, headaches, and a sore throat. This Hairy Oral Leukoplakia
disorder is different from chronic fatigue syndrome, which Hairy oral leukoplakia is an unusual manifestation of a
has an unknown etiology.  productive EBV infection of epithelial cells characterized
Epstein-Barr Virus–Induced Lymphoproliferative by lesions of the tongue and mouth. It is an opportunistic
Diseases manifestation that occurs in patients with AIDS. 
On infection with EBV, people lacking T-cell immunity are
likely to suffer life-threatening polyclonal leukemia-like B-cell LABORATORY DIAGNOSIS
proliferative disease and lymphoma instead of infectious mono-
nucleosis. Men with congenital deficiencies of T-cell function EBV-induced infectious mononucleosis is diagnosed on the
are likely to suffer life-threatening X-linked lymphoprolifera- basis of the symptoms (Box 43.10), the finding of atypi-
tive disease. One such X-linked genetic defect in a T-cell gene cal lymphocytes, the presence of lymphocytosis (mono-
(signaling lymphocyte activation molecule [SLAM]–associ- nuclear cells constituting 60% to 70% of the white blood
ated protein) prevents the T cell from controlling B-cell growth cell count, with 30% atypical lymphocytes), heterophile
during a normal immune response to antigen or because of antibody, antibody to viral antigens, and viral DNA. Virus
EBV. Transplant recipients undergoing immunosuppressive isolation is not practical. PCR and DNA probe analysis for
treatment are at high risk for posttransplant lymphopro- the viral genome and amount of virus (virus load) and
liferative disease, instead of infectious mononucleosis, after immunofluorescent identification of viral antigens are used
exposure to the virus or on reactivation of latent virus. The to detect and follow the course of infection.
disease dissipates on reduction of immunosuppression. Similar
diseases are seen in patients with AIDS. Atypical lymphocytes are probably the earliest detect-
able indication of an EBV infection. These cells appear with
the onset of symptoms and disappear with resolution of the
disease.

Heterophile antibody results from the nonspecific,
mitogen-like activation of B cells by EBV and the production

444 SECTION 5  •  Virology

TABLE 43.4  Serologic Profile for Epstein-Barr Virus Infection

Susceptible Mononucleosis Heterophile EBV-SPECIFIC ANTIBODIES Comment
Acute primary infection − A­ ntibodies VCA-IgM VCA-IgG EA EBNA
Chronic primary infection + − − −− Heterophile antibody
Past infection − − + + ±− present early in disease,
Reactivation infection − + − + +− anti-VCA and anti-MA
Burkitt lymphoma − − − + −+ present during disease,
Nasopharyngeal carcinoma − − − + ++ and anti-EBNA only
− − − + ++ present during conva-
− − + ++ lescence
−

EA, Early antigen; EBNA, Epstein-Barr nuclear antigen; IgG, immunoglobulin G; IgM, immunoglobulin M; MA, membrane antigen; VCA, viral capsid antigen.
Modified from Balows, A., Hausler, W.J., Lennette, E.H. (Eds.), 1988. Laboratory Diagnosis of Infectious Diseases: Principles and Practices. Springer-Verlag, New

York, NY.

of a wide repertoire of antibodies. These antibodies include BOX 43.11  Disease Mechanisms of
an IgM heterophile antibody that recognizes the Paul-Bun- Cytomegalovirus
nell antigen on sheep, horse, and bovine erythrocytes but
not that on guinea pig kidney cells. The heterophile anti- Acquired from blood, tissue, and most body secretions.
body response can usually be detected by the end of the first Causes productive infection of macrophages, epithelial cells, and
week of illness and lasts for as long as several months. It is
an excellent indication of EBV infection in adults but is not other cells.
as reliable in children or infants. The horse cell (Monospot) Establishes latency in hematopoietic stem cells and monocytes
test and ELISA are rapid and widely used for detection of the Cell-mediated immunity is required for resolution and mainte-
heterophile antibody.
nance of latency and contributes to symptoms.
Serologic tests for antibody to viral antigens are a more The role of antibody is limited.
dependable method than heterophile antibody to confirm Suppression of cell-mediated immunity allows recurrence and
the diagnosis of EBV mononucleosis (Table 43.4; see Fig.
43.15). EBV infection is indicated by the finding of any of severe disease.
the following: (1) IgM antibody to the VCA, (2) the pres- CMV generally causes subclinical infection.
ence of VCA antibody and the absence of EBNA antibody,
or (3) elevation of antibodies to VCA and EA. The finding of CMV, Cytomegalovirus.
both VCA and EBNA antibodies in serum indicates that the
person had a previous infection. Generation of antibody to is particularly important as an opportunistic pathogen
EBNA requires lysis of the infected cell and usually indicates in immunocompromised patients.
T-cell control of active disease and its presence indicates
resolution of the disease.  STRUCTURE AND REPLICATION
CMV is a member of the subfamily Betaherpesvirinae. It has
TREATMENT, PREVENTION, AND CONTROL the largest genome of the HHVs. Only a quarter of its genes
No effective treatment or vaccine is available for EBV disease. are required for replication, whereas most of the other genes
After being activated by the viral protein kinase, acyclovir manipulate host interactions and the immune response. In
will reduce viral shedding but not disease. The ubiquitous contrast to the traditional definition of a virus, which states
nature of the virus and the potential for asymptomatic shed- that a virion particle contains DNA or RNA, CMV carries
ding make control of infection difficult. However, infection specific mRNAs into the cell in the virion particle to facili-
elicits lifelong immunity. Therefore the best means of pre- tate infection. Human CMV replicates only in human cells.
venting infectious mononucleosis is exposure to the virus Fibroblasts, epithelial cells, granulocytes, macrophages,
early in life because the disease is more benign in children.  and other cells are permissive for CMV replication. Virus
replication is much slower than for HSV, and CPE may not
Cytomegalovirus be seen for 7 to 14 days. This may facilitate the establish-
ment of latent infection in myeloid stem cells, monocytes,
CMV is a common human pathogen, infecting approxi- lymphocytes, the stromal cells of the bone marrow, or other
mately 1% of all newborns and at least 50% to 80% of adults cells. 
by age 40. It is the most common viral cause of congenital
defects with 1 in 150 children born infected with the virus PATHOGENESIS AND IMMUNITY
and 1 in 750 born with or will develop permanent disabili- CMV is an excellent parasite and readily establishes per-
ties caused by congenital CMV. Although usually causing sistent and latent infections rather than an extensive lytic
mild or asymptomatic disease in children and adults, CMV infection (Box 43.11). CMV is highly cell associated and is
spread throughout the body within infected cells, especially

43  •  Human Herpesviruses 445

Clinical Case 43.3  A Role for TABLE 43.5  Sources of Cytomegalovirus Infection
Cytomegalovirus in Medulloblastoma
Age Group Source
CMV is present in a large percentage of medulloblastomas,
which is the most common malignant brain tumor in Neonate Transplacental transmission, intrauterine infections,
children. In a study of these tumors by Baryawno and asso- Baby or child cervical secretions
ciates (J Clin Invest 121:4043–4055, 2011), CMV induced
inflammation and promoted the production of interleukin Body secretions: breast milk, saliva, tears, urine
6, vascular endothelial growth factor, and prostaglandin
E2, which promoted the growth of the medulloblastoma Adult Sexual transmission (semen), blood transfusion,
cells. Treatment with ganciclovir and a nonsteroidal anti- organ graft
inflammatory drug stopped the growth of these cells.
CMV, Cytomegalovirus. BOX 43.12  Epidemiology of
Cytomegalovirus Infection
lymphocytes and leukocytes. The virus establishes latency
in hematopoietic progenitor cells in the bone marrow and Disease/Viral Factors
monocytes. The virus reactivates on immunosuppression
(e.g., corticosteroids, infection with HIV) and possibly by Virus causes lifelong infection.
allogeneic stimulation (i.e., the host response to transfused Recurrent disease is source of contagion.
or transplanted cells) and replicates in ductal epithelia to be Virus causes asymptomatic shedding. 
shed in saliva, urine, breast milk, semen and other body flu-
ids. CMV is shed sporadically throughout life. Transmission

Cell-mediated immunity is essential for resolving and Transmission occurs via blood, organ transplants, and all secre-
controlling the outgrowth of CMV infection. However, CMV tions (urine, saliva, semen, cervical secretions, breast milk, and
is an expert at immune evasion and has several means for tears).
evading innate and immune responses. The virus prevents
antigen presentation to both CD8 cytotoxic T cells and CD4 Virus is transmitted orally and sexually, in blood transfusions, in
T cells by preventing the expression of MHC I molecules on tissue transplants, in utero, at birth, and by nursing. 
the cell surface and by interfering with cytokine-induced
expression of MHC II molecules on antigen-presenting cells Who Is at Risk?
(including the infected cells). A viral protein also blocks NK-
cell attack of CMV-infected cells. Similar to EBV, CMV also Babies
encodes an IL-10 analog that would inhibit TH1 protective Babies of mothers who experience seroconversion during term
immune responses. are at high risk for congenital defects

CMV is a common passenger in many children and Sexually active people
adults and may reactivate throughout life to cause tran- Blood and organ recipients
sient immune responses and inflammation and influence Burn victims
the health of the individual. CMV has been implicated as a Immunocompromised people: symptomatic and recurrent
cofactor for medulloblastoma, leukemia, and other diseases
(Clinical Case 43.3).  disease 
EPIDEMIOLOGY AND CLINICAL SYNDROMES
In most cases, CMV replicates and is shed without causing Geography/Season
symptoms (Table 43.5). Activation and replication of CMV
in the kidney and secretory glands promote its secretion Virus is found worldwide.
in urine and bodily secretions. CMV can be isolated from There is no seasonal incidence. 
urine, blood, throat washings, saliva, tears, breast milk,
semen, stool, amniotic fluid, vaginal and cervical secre- Modes of Control
tions, and tissues obtained for transplantation (Box 43.12
and Table 43.6). Virus can be transmitted to other individu- Antiviral drugs are available for serious disease.
als by means of blood transfusions and organ transplants. Screening potential blood and organ donors for cytomegalovirus
The congenital, oral, and sexual routes, blood transfusion,
and tissue transplantation are the major means by which reduces transmission of virus.
CMV is transmitted. CMV disease is an opportunistic dis-
ease, rarely causing symptoms in the immunocompetent Congenital Infection
host but causing serious disease in an immunosuppressed CMV is the most prevalent viral cause of congenital disease.
or immunodeficient person, such as a patient with AIDS or Approximately 15% of stillborn babies are infected with
a neonate (Fig. 43.16). CMV. Almost 1% of all newborns in the United States are
infected with CMV before birth, and a large percentage of
babies are infected within the first months of life. Of these,
80% may shed virus for long periods with as many as 25% of
them having hearing, eyesight, and IQ deficits that develop
over time. CMV is the most common infectious cause of con-
genital hearing loss in the United States, and vision loss and
mental retardation are also common consequences of con-
genital CMV infection. Approximately 1/10,000 live births
will be born with cytomegalic inclusion disease. Disease
signs include small size, thrombocytopenia, microcephaly,
intracerebral calcification, jaundice, hepatosplenomegaly,
and rash. The risk for serious birth defects is extremely high
for infants born to mothers who had primary CMV infec-
tions during their pregnancies.

446 SECTION 5  •  Virology

TABLE 43.6  Cytomegalovirus Syndromes Infection in Children and Adults
Approximately 40% of adolescents are infected with
Tissue Children/Adults Immunosuppressed CMV, but this number increases to 50% to 85% of adults
Predominant Asymptomatic Patients in the United States by the age of 40. CMV is more preva-
lent among people in low socioeconomic brackets living
presentation — Disseminated disease, in crowded conditions and in people living in developing
Eyes — severe disease countries. CMV is a sexually transmitted disease, and
Lungs 90% to 100% of patients attending sexually transmitted
— Retinitis disease clinics are infected. The titer of the CMV in semen is
Gastrointestinal the highest of that in any body secretion.
tract Pneumonia, pneu-
monitis Although most CMV infections acquired in young adult-
Nervous system hood are asymptomatic, patients may show a heterophile-
Esophagitis, colitis negative mononucleosis syndrome. The symptoms of
Lymphoid system CMV disease are similar to those of EBV infection but with less
Polyneuritis, myelitis Meningitis and severe pharyngitis and lymphadenopathy (see Fig. 43.16).
Major organs encephalitis, myelitis Although the presence of CMV-infected cells promotes a
Neonates Mononucleosis syn- T-cell outgrowth (atypical lymphocytosis) similar to that
drome, posttrans- Leukopenia, lympho- seen in EBV infection, heterophile antibody is not present.
fusion syndrome cytosis Because CMV does not infect the B cell, nor does it stimulate
or activate the B cell, there is no heterophile antibody. CMV
Carditis,a hepatitisa Hepatitis disease should be suspected in a patient who has heterophile-
— negative mononucleosis or in whom there are signs of hepa-
Deafness, intracere- titis but results of tests for hepatitis A, B, and C are negative. 
bral calcification, Transmission via Transfusion and Transplantation
microcephaly, Transmission of CMV by blood most often results in an
mental retardation asymptomatic infection; if symptoms are present, they typi-
cally resemble those of mononucleosis. Fever, splenomeg-
aComplication of mononucleosis or posttransfusion syndrome. aly, and atypical lymphocytosis usually begin 3 to 5 weeks
after transfusion. Pneumonia and mild hepatitis may also
ASYMPTOMATIC CARRIER occur. CMV may also be transmitted by organ transplan-
tation (e.g., kidneys, bone marrow), and CMV infection is
Mononucleosis often reactivated in transplant recipients during periods of
(Heterophile Ab negative) intense immunosuppression. 
Infection in the Immunocompromised Host
CMV Normal CYTOMEGALIC CMV is a prominent opportunistic infectious agent. In
INCLUSION immunocompromised people, it causes symptomatic pri-
Neonate of DISEASE mary or recurrent disease (see Table 43.6).
seronegative
mother CMV disease of the lung (pneumonia and pneumoni-
tis) is a common outcome in immunosuppressed patients
AIDS, and can be fatal if not treated. CMV often causes retinitis,
immunosuppressed colitis, or esophagitis in patients who are severely immu-
nodeficient (e.g., patients with AIDS). Interstitial pneumo-
MULTISITE nia and encephalitis also may be caused by CMV but may
SYMPTOMATIC be difficult to distinguish from infections caused by other
DISEASE opportunistic agents. CMV esophagitis may mimic candidal
esophagitis. A smaller percentage of immunocompromised
Fig. 43.16  Outcomes of cytomegalovirus (CMV) infections. The out- patients may experience CMV infection of the gastrointesti-
come of CMV infection depends very heavily on the immune status of nal tract. Patients with CMV colitis usually have diarrhea,
the patient. Ab, Antibody; AIDS, acquired immunodeficiency syndrome. weight loss, anorexia, and fever. Effective anti-HIV therapy
has reduced the incidence of these diseases.
Fetuses are infected by the virus in the mother’s blood
(primary infection) or by virus ascending from the cervix CMV is also responsible for the failure of many kidney
(after a recurrence). Congenital CMV infection is best docu- transplants. The graft may succumb to virus replication
mented by isolation of the virus from the infant’s urine dur- or cytolytic immune responses to the viral antigens. CMV
ing the first week of life.  can also infect the immunosuppressed host. 
Perinatal Infection
In the United States, approximately 60% of pregnant LABORATORY DIAGNOSIS
women are infected with CMV at term and are likely to expe- Histology
rience reactivation of the virus during pregnancy. Approxi- The histologic hallmark of CMV infection is the cytome-
mately half the neonates born from an infected mother galic cell, which is an enlarged cell (25 to 35 mm in
acquire CMV infection and become excreters of the virus at
3 to 4 weeks of age. Neonates may also acquire CMV from
maternal milk or colostrum. Perinatal infection causes no
clinically evident disease in healthy full-term infants. Sig-
nificant clinical infection may occur in premature infants
who acquire CMV from transfused blood, usually resulting
in pneumonia and hepatitis. 

43  •  Human Herpesviruses 447

diameter) that contains a dense, central, “owl’s eye,” More rapid results are achieved by centrifuging a
basophilic intranuclear inclusion body (Fig. 43.17 and patient’s sample onto cells grown on a coverslip within a
Table 43.7). Such infected cells may be found in any tissue shell vial. Specimens are examined after 1 to 2 days of incu-
of the body and in urine and are thought to be epithelial in bation by indirect immunofluorescence for the presence of
origin. The inclusions are readily seen with Papanicolaou one or more of the immediate early viral antigens. 
or hematoxylin-eosin staining.  Serology
Antigen and Genome Detection Seroconversion is usually an excellent marker for primary
A rapid, sensitive diagnosis can be obtained by detection of CMV infection. Titers of CMV-specific IgM antibody may be
viral antigen, using immunofluorescence or an ELISA, or very high in patients with AIDS. However, CMV-specific
the viral genome, using PCR and related techniques in cells IgM antibody may also develop during the reactivation of
of a biopsy, blood, bronchoalveolar lavage, or urine sample CMV; therefore it is not a dependable indicator of primary
(see Chapter 5). Distinction of active CMV from latent CMV infection. 
requires detection of CMV mRNA or large amounts of DNA
in blood.  TREATMENT, PREVENTION, AND CONTROL
Culture Ganciclovir (dihydroxypropoxymethyl guanine), valgan-
CMV is grown in diploid fibroblast cell cultures and nor- ciclovir (valyl ester of ganciclovir), cidofovir, and foscar-
mally must be maintained for at least 4 to 6 weeks because net (phosphonoformic acid) have been approved by the
the characteristic CPE develops very slowly in specimens U.S. Food and Drug Administration (FDA) for the treatment
with very low titers of the virus. Isolation of CMV is espe- of specific diseases resulting from CMV infections of immu-
cially reliable in immunocompromised patients, who often nosuppressed patients (see Box 43.5). Ganciclovir is struc-
have high titers of virus in their secretions. For example, in turally similar to ACV; it is phosphorylated and activated
the semen of patients with AIDS, titers of viable virus may by a CMV-encoded protein kinase, inhibits the viral DNA
be greater than 106. polymerase, and causes DNA termination (see Chapter
40). Ganciclovir is more toxic than ACV. Ganciclovir can
Fig. 43.17  Cytomegalovirus-infected cell with basophilic nuclear be used to treat severe CMV infections in immunocompro-
inclusion body. mised patients. Valganciclovir is a prodrug of ganciclovir
that can be taken orally, is converted to ganciclovir in the
TABLE 43.7  Laboratory Tests for Diagnosing liver, and has better bioavailability than ganciclovir. Cido-
Cytomegalovirus Infection fovir is a phosphorylated cytidine nucleoside analog that
does not require a viral enzyme for activation. Foscarnet is
Test Finding a simple molecule that inhibits the viral DNA polymerase
Cytology and by mimicking the pyrophosphate portion of nucleotide
“Owl’s-eye” basophilic nuclear inclusion body triphosphates.
­histologya Antigen detection
Cell culture In situ DNA probe hybridization CMV spreads mainly by sexual, tissue transplantation,
PCRb and transfusion routes; and spread by these means is pre-
Serology ventable. Semen is a major vector for the sexual spread of
Cytologic effect in human diploid fibroblasts (slow) CMV to both heterosexual and homosexual contacts. The
Immunofluorescence detection of early antigens use of condoms or abstinence would limit viral spread.
Transmission of the virus can also be reduced through the
(faster) screening of potential blood and organ donors for CMV
PCR (fastest) seronegativity. Screening is especially important for donors
of blood transfusions to be given to infants. Although con-
Only for primary infection genital and perinatal transmission of CMV cannot effec-
tively be prevented, a seropositive mother is least likely to
aSamples taken for analysis include urine, saliva, blood, bronchoalveolar produce a baby with symptomatic CMV disease. No vaccine
lavage specimens, and tissue biopsy specimens. for CMV is available. 

bmost accepted approach. Human Herpesviruses 6 and 7
PCR, Polymerase chain reaction.
The two variants of HHV-6, HHV-6A and HHV-6B, and
HHV-7, are members of the genus Roseolovirus of the sub-
family Betaherpesvirinae. HHV-6 was first isolated from the
blood of patients with AIDS and grown in T-cell cultures.
It was identified as a herpesvirus because of its charac-
teristic morphology within infected cells. Similar to CMV,
HHV-6 is lymphotropic and ubiquitous. At least 45% of the
population is seropositive for HHV-6B and HHV-7 by age 2
years, and almost 100% by adulthood. HHV-6B and HHV-7
cause a common disease of children, exanthem subitum,

448 SECTION 5  •  Virology

commonly known as roseola. HHV-7 was isolated in a sim- BOX 43.13  Clinical Summaries
ilar manner from the T cells of a patient with AIDS who was
also infected with HHV-6. Herpes Simplex Virus

PATHOGENESIS AND IMMUNITY Primary oral herpes: A 5-year-old boy has an ulcerative rash with
HHV-6 infection occurs very early in life. The virus repli- vesicles around the mouth. Vesicles and ulcers are also present
cates in the salivary gland, is shed, and is transmitted in within the mouth. Results of a Tzanck smear show multinucle-
saliva. ated giant cells (syncytia) and Cowdry type A inclusion bodies.
The lesions resolve after 18 days.
HHV-6 primarily infects lymphocytes, especially CD4 T
cells. HHV-6 establishes a latent infection in hematopoietic Recurrent oral HSV: A 22-year-old medical student studying for
progenitor cells and T cells but may replicate on activation examinations feels a twinge at the crimson border of his lip and
of the cells. Cells in which the virus is replicating appear 24 hours later has a single vesicular lesion at the site.
large and refractile and have occasional intranuclear and
intracytoplasmic inclusion bodies. Similar to the replication Recurrent genital HSV: A sexually active 32-year-old woman
of CMV, the replication of HHV-6 is controlled by cell-medi- has a recurrence of ulcerative vaginal lesions with pain, itch-
ated immunity. Similar to CMV, the virus is likely to become ing, dysuria, and systemic symptoms 48 hours after being
activated in patients with AIDS or other lymphoprolifera- exposed to ultraviolet B light while skiing. The lesions resolve
tive and immunosuppressive disorders and cause opportu- within 8 days. Results of a Papanicolaou smear show multi-
nistic disease.  nucleated giant cells (syncytia) and Cowdry type A inclusion
bodies.
CLINICAL SYNDROMES
Exanthem subitum, or roseola, is caused by either HHV- Encephalitis HSV: A patient has focal neurologic symptoms and
6B or HHV-7 and is one of the five classic childhood exan- seizures. Magnetic resonance imaging results show destruction
thems previously mentioned (Box 43.13 and Fig. 43.18). of a temporal lobe. Erythrocytes are present in the cerebro-
It is characterized by the rapid onset of high fever of a few spinal fluid, and polymerase chain reaction is positive for
days’ duration, which is followed by a rash on the trunk and viral DNA. 
face, and then it spreads and lasts only 24 to 48 hours. The
presence of infected T cells or the activation of delayed-type Varicella-Zoster Virus
hypersensitivity T cells in the skin may be the cause of the
rash. The disease is effectively controlled and resolved by Varicella (chickenpox): A 5-year-old boy develops a fever and
cell-mediated immunity, but the virus establishes a lifelong a maculopapular rash on his abdomen 14 days after meet-
latent infection of T cells. Although usually benign, HHV-6 ing with his cousin, who also developed the rash. Successive
is the most common cause of febrile seizures in childhood crops of lesions appear for 3 to 5 days, and the rash spreads
(aged 6 to 24 months). p­ eripherally.

HHV-6 may also cause a mononucleosis syndrome and Zoster (shingles): A 65-year-old woman has a belt of vesicles
lymphadenopathy in adults and may be a cofactor in the along the thoracic dermatome and experiences severe pain
pathogenesis of AIDS. Similar to CMV, HHV-6A and HHV- localized to the region. 
6B may reactivate in transplant patients and contribute to
graft failure. HHV-6A and HHV-6B have also been associ- Epstein-Barr Virus
ated with multiple sclerosis, Alzheimer disease, and chronic
fatigue syndrome. HHV-6 infection or reactivation is also Infectious mononucleosis: A 23-year-old college student de-
associated with the drug reaction with eosinophilia and sys- velops malaise, fatigue, fever, swollen glands, and pharyngitis.
temic symptoms (DRESS) syndrome. After empirical treatment with ampicillin for a sore throat, a
rash appears. Heterophile antibody and atypical lymphocytes
In approximately 1% of individuals in the United States are detected from blood. 
and the United Kingdom, HHV-6 is integrated into the telo-
meres of every chromosome and can be genetically trans- Cytomegalovirus
mitted to offspring. The virus may be reactivated by certain
drugs (including antibiotics and steroids), produce virus, Congenital CMV disease: A neonate exhibits microcephaly,
and may cause fatigue, cognitive dysfunction, and other hepatosplenomegaly, and rash. Intracerebral calcifica-
problems.  tion is noted on a radiograph. The mother had symptoms
similar to mononucleosis during the third trimester of her
­pregnancy. 

Human Herpesvirus 6

Roseola (exanthem subitum): A 4-year-old child experiences
a rapid onset of high fever that lasts for 3 days and then
suddenly returns to normal. Two days later, a maculopapu-
lar rash appears on the trunk and spreads to other parts of
the body.

CMV, Cytomegalovirus; HSV, herpes simplex virus.

Other Human Herpesviruses HHV-6 Incubation Abrupt start of No Fever Recovery
4-7 days HIGH FEVER RASH without
HUMAN HERPESVIRUS 8 (KAPOSI SARCOMA– (103° F to 105° F) APPEARS
ASSOCIATED HERPESVIRUS) complications
HHV-8 DNA sequences were discovered in biopsy speci- 4 days
mens of Kaposi sarcoma, primary effusion lymphoma
(a rare type of B-cell lymphoma), and multicentric Fig. 43.18  Time course of symptoms of exanthem subitum (roseola)
caused by human herpesvirus 6 (HHV-6). Compare these symptoms
and this time course with those of fifth disease, which is caused by par-
vovirus B19 (see Chapter 45).

43  •  Human Herpesviruses 449

Castleman disease through the use of PCR analysis. Kimberlin, D.W., 2004. Neonatal herpes simplex virus infection. Clin.
Kaposi sarcoma is one of the characteristic opportunistic Microbiol. Rev. 17, 1–13.
diseases associated with AIDS. Genome sequence analysis
showed that the virus was unique and a member of the sub- Rouse, B.T., 1992. Herpes Simplex Virus: Pathogenesis, Immunobiology
family Gammaherpesvirinae. Similar to EBV, the B cell is and Control, Current Topics in Microbiology and Immunology, vol. 179.
the primary target cell for HHV-8, but the virus also infects Springer-Verlag, Berlin, New York.
a limited number of endothelial cells, monocytes, and epi-
thelial and sensory nerve cells. Within the Kaposi sarcoma Varicella-Zoster Virus
tumors, endothelial spindle cells contain the virus. Abendroth, A., et  al., 2010. Varicella-Zoster Virus Infections, Curr Top

HHV-8 encodes several proteins that resemble human Microbiol Immunol, vol. 342. Springer-Verlag, Berlin, Heidelberg.
proteins and promote the growth and prevent apoptosis of Chia-Chi Ku, V., Besser, J., Abendroth, A., 2005. Varicella-zoster virus
the infected and surrounding cells. These proteins include
an IL-6 homolog (growth and antiapoptosis), a Bcl-2 ana- pathogenesis and immunobiology: new concepts emerging from inves-
log (antiapoptosis), chemokines, and a chemokine receptor. tigations with the SCIDhu mouse model. J. Virol. 79, 2651–2658.
These proteins can promote growth and development of Gnann, J.W., Whitley, R.J., 2002. Herpes zoster. N. Engl. J. Med. 347,
polyclonal Kaposi sarcoma cells in AIDS patients and oth- 340–346.
ers. HHV-8 DNA is present and is associated with peripheral
blood lymphocytes, most likely B cells, in approximately Epstein-Barr Virus
10% of immunocompetent people. HHV-8 is more preva- Basgoz, N., Preiksaitis, J.K., 1995. Post-transplant lymphoproliferative dis-
lent in certain geographic areas (Italy, Greece, Africa) and
in patients with AIDS. Kaposi sarcoma is the most common order. Infect. Dis. Clin. North. Am. 9, 901–923.
cancer in sub-Saharan Africa. The virus is most likely a sex- Bennett, N.J., 2017. Pediatric Mononucleosis and Epstein-Barr Virus Infec-
ually transmitted disease but may be spread by other means.
tion. https://emedicine.medscape.com/article/963894-overview#a1.
Herpesvirus simiae (B virus) (subfamily Alphaher- Munz, C., 2015. Epstein Barr Virus Volumes 1 and 2. Curr. Topic. Micro-
pesvirinae, the simian counterpart of HSV) is indigenous
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PCR or serologic tests can be used to establish the diagnosis Thorley-Lawson, D.A., 1996. Epstein-Barr virus and the B cell: that’s all it
of B-virus infections. Virus isolation requires special facilities. takes. Trends. Microbiol. 4, 204–208.
Thorley-Lawson, D.A., Babcock, G.J., 1999. A model for persistent infec-
  For a case study and questions see Student­Consult.com tion with Epstein-Barr virus: the stealth virus of human B cells. Life. Sci.
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Case Studies and Questions swollen cervical lymph nodes, and increasing fatigue. The
patient also notes some discomfort in the left upper quad-
A 2-year-old child with fever for 2 days has not been eating rant of the abdomen. The sore throat, lymphadenopathy,
and has been crying often. On examination, the physician and fever gradually resolve over the next 2 weeks, but
notes that the mucous membranes of the mouth are cov- the patient’s full energy level does not return for another
ered with numerous shallow, pale ulcerations. A few red 6 weeks.
papules and blisters are also observed around the border 7. What laboratory tests would confirm the diagnosis of
of the lips. The symptoms worsen over the next 5 days and
then slowly resolve, with complete healing after 2 weeks. EBV-induced infectious mononucleosis and distinguish
1 . The physician suspects that this is an HSV infection. it from CMV infection?
8. To what characteristic diagnostic feature of the disease
How would the diagnosis be confirmed? does mononucleosis refer?
2. How could you determine whether this infection was 9. What causes the swollen glands and fatigue?
10. Who is at greatest risk for a serious outcome of an EBV
caused by HSV-1 or HSV-2? infection? What is the outcome? Why?
3 . What immune responses were most helpful in resolving Thought Question: The herpesviruses are ubiquitous
and establish lifelong latent-recurrent infections. Immune
this infection, and when were they activated? responses are continuously activated to prevent recur-
4. HSV escapes complete immune resolution by causing rence. The viruses recur with different frequency depend-
ing on the person, and although the recurrence may be
latent and recurrent infections. What was the site of asymptomatic, it will elicit immune and inflammatory
latency in this child, and what might promote future responses. Consider for a moment how this can influence
recurrences? the health of the individual over his or her lifetime. The
5 . What were the most probable means by which the child immune stimulation may be helpful, harmful, or have no
was infected with HSV? consequence. The presence of the virus within cells dur-
6. Which antiviral drugs are available for the treatment of ing latency may have no effect or may alter the growth or
HSV infections? What are their targets? Were they indi- function of the cell.
cated for this child? Why or why not?
A 17-year-old high school student has had low-grade
fever and malaise for several days, followed by sore throat,

449.e1

44 Poxviruses

A goat herder has a large vesicular lesion on his index antagonist notices a large number of umbilicated
finger. papules on the skin of her upper thighs.
1 . How does the orf virus infecting this individual resemble 5 . How does the molluscum contagiosum virus (MCV)

smallpox? resemble and differ from other poxviruses?
2. What was the source, and how was it acquired? 6 . What was the source, and how was it acquired?
3. How is replication of this virus different from other DNA 7 . What other conditions increase susceptibility to this

viruses? infection and presentation?
4. Why was it possible to eradicate wild-type smallpox virus?
 Answers to these questions are available on Student
A 57-year-old woman who has rheumatoid arthri- Consult.com.
tis and treated with a tumor necrosis factor (TNF)

Summaries Clinically Significant Organisms ᑏᑏ Molluscum contagiosum stimulates Diagnosis
cell growth to cause wartlike growth; ᑏᑏ Polymerase chain reaction genome
POXVIRUSES only infects humans
analysis of lesion fluid
Trigger Words ᑏᑏ Smallpox: lytic, only infects humans,
vesicles appear all at once, bioterror Treatment, Prevention, and Control
Molluscum, smallpox, zoonosis, vaccinia agent ᑏᑏ Vaccinia virus as vaccine for smallpox
vaccine, cytoplasmic replication ᑏᑏ Quarantine
ᑏᑏ Vaccinia, orf: lytic viruses, zoonotic
Biology, Virulence, and Disease
Epidemiology
ᑏᑏ Very large, enveloped with complex
morphology, linear DNA genome ᑏᑏ Smallpox transmitted by aerosols,
fused at ends, virus encodes DNA- direct contact; all others only by
dependent RNA and DNA-dependent contact
DNA polymerases

ᑏᑏ Cell-mediated immunity essential for
control

The poxviruses include the human viruses variola (small- smallpox to be acquired and used by a terrorist has been the
pox) (genus Orthopoxvirus) and molluscum contagiosum impetus to renew interest in developing new smallpox vac-
(genus Molluscipoxvirus) and some viruses that naturally cine programs and antiviral drugs.
infect animals but can cause incidental infection in humans
(zoonoses). Many of these viruses share antigenic determi- On a positive note, the vaccinia and canarypox viruses
nants with smallpox, allowing the use of an animal poxvi- have found a beneficial use as gene delivery vectors and for
rus for a human vaccine. the development of hybrid vaccines. These hybrid viruses
contain and express the genes of other infectious agents,
In 18th century England, smallpox accounted for 7% and infection results in immunization against both agents.
to 12% of all deaths and the deaths of one-third of chil-
dren. However, the development of the first live vaccine in Structure and Replication
1796 and the later worldwide distribution of this vaccine
led to eradication of smallpox by 1980. As a result, refer- Poxviruses are the largest viruses and are almost visible on
ence stocks of smallpox virus in two World Health Orga- light microscopy (Box 44.1). They measure 230 × 300 nm
nization (WHO) laboratories were destroyed in 1996 after and are ovoid to brick shaped with a complex morphology.
an international agreement to do so was reached. Unfor- The poxvirus virion particle must carry many enzymes,
tunately, smallpox did not disappear. Stocks of the virus including a deoxyribonucleic acid (DNA)-dependent ribo-
still exist in the United States and Russia. While the world nucleic acid (RNA) polymerase, to allow viral messenger
was successfully eliminating natural smallpox, the former RNA (mRNA) synthesis to occur in the cytoplasm. The viral
Union of Soviet Socialist Republics (USSR) was stockpil- genome consists of a large, double-stranded, linear DNA
ing immense amounts of weaponized smallpox virus for that is fused at both ends. The structure and replication of
biowarfare. Smallpox is considered a category A agent by vaccinia virus is representative of the other poxviruses (Fig.
the U.S. Centers for Disease Control and Prevention (CDC), 44.1). The genome of vaccinia virus consists of approxi-
along with anthrax, plague, botulism, tularemia, and viral mately 189,000 base pairs.
hemorrhagic fevers because of their great potential as bio-
terrorism-biowarfare agents capable of large-scale dissemi- The replication of poxviruses is unique among the DNA-
nation and serious disease. The potential for these stocks of containing viruses in that the entire multiplication cycle
450

44  •  Poxviruses 451

takes place within the host cell cytoplasm (Fig. 44.2). Thus Pathogenesis and Immunity
poxviruses must encode the enzymes required for mRNA
and DNA synthesis and activities other DNA viruses nor- After being inhaled, smallpox virus replicates in the upper
mally obtain from the host cell. respiratory tract (Fig. 44.3). Dissemination occurs via
lymphatic and cell-associated viremic spread. Internal
After binding to a cell-surface receptor, the poxvirus and dermal tissues are inoculated after a second, more
outer envelope fuses with cellular membranes, either at intense viremia, causing simultaneous eruption of the
the cell surface or within the cell. Early gene transcription characteristic “pocks.” Molluscum contagiosum and the
is initiated on removal of the outer membrane. The virion other poxviruses, however, are acquired through direct
core contains a specific transcriptional activator and all contact with lesions and do not spread extensively. Mol-
the enzymes necessary for transcription, including a mul- luscum contagiosum stimulates cell growth and causes
tisubunit RNA polymerase, as well as enzymes for poly- a wartlike lesion rather than a lytic infection.
adenylate addition and capping mRNA. Among the early
proteins produced is an uncoating protein (uncoatase) that The poxviruses encode many proteins that facilitate their
removes the core membrane, liberating viral DNA into replication and pathogenesis in the host. They include pro-
the cell cytoplasm. Viral DNA then replicates in electron- teins that initially stimulate host cell growth and then lead
dense cytoplasmic inclusions (Guarnieri inclusion bodies), to cell lysis and viral spread.
referred to as factories. Late viral mRNA for structural,
virion, and other proteins is produced after DNA replica- Cell-mediated immunity is essential for resolving a pox-
tion. In poxviruses, unlike other viruses, the membranes virus infection. However, up to 30% of the genome of pox-
assemble around the core factories. Approximately 10,000 viruses is devoted to activities that help the virus evade
viral particles are produced per infected cell. Different forms immune control, including proteins that impede the inter-
of viruses are released by exocytosis or on cell lysis, but both feron, complement, inflammatory, antibody, and cell-medi-
are infectious. ated protective responses. In addition, these viruses can
spread cell to cell and avoid antibody. The disease mecha-
MCV infection proceeds similarly to the other poxviruses nisms of poxviruses are summarized in Box 44.2. 
but is restricted to keratinocytes, stimulates the growth of
the cell, prevents apoptosis, inhibits inflammation, and is Epidemiology
not cytolytic. Like human papillomaviruses, the virus is
released when the keratinocyte matures and senesces.  Smallpox and molluscum contagiosum are strictly human
viruses. Smallpox is transmitted by aerosols and by contact
BOX 44.1  Unique Properties of Poxviruses with lesion material or by a fomite. Molluscum contagiosum
is spread by direct contact (e.g., sexual contact, wrestling,
Largest, most complex viruses. self-inoculation) or by fomites (e.g., towels). In contrast,
Have complex, oval- to brick-shaped morphology with internal the natural hosts for the other poxviruses are vertebrates
other than humans (e.g., cow, sheep, goats), and they infect
structure. humans only through accidental or occupational exposure
Have a linear, double-stranded DNA genome with fused ends. (zoonosis). A recent outbreak of monkeypox in the United
DNA viruses that replicate in the cytoplasm. States is such an example. The infected individuals had
Encodes and carries all proteins necessary for mRNA synthesis. purchased prairie dog pets that had been in contact with
Also encodes proteins for functions such as DNA synthesis, nu- Gambian giant rats, which were the probable source of the
virus. The revival of smallpox vaccination of military per-
cleotide scavenging, and immune escape mechanisms. sonnel has brought with it incidences of vaccine-mediated
Assembled in inclusion bodies (Guarnieri bodies; factories), where (vaccinia) disease in contacts.

it acquires its outer membranes.

Surface Envelope
tubules Lateral body

Outer membrane

Core (viral DNA
and protein)

Core membrane

AB

Fig. 44.1  (A) Structure of the vaccinia virus. Within the virion, the core assumes the shape of a dumbbell because of the large lateral bodies. Virions
have a double membrane; the “outer membrane” assembles around the core in the cytoplasm, and the virus leaves the cell by exocytosis or on cell lysis.
(B) Electron micrographs of orf virus. Note its complex structure.

452 SECTION 5  •  Virology

Virus Cell Smallpox (variola) was very contagious and, as just
Adsorption membrane noted, was spread primarily by the respiratory route. It was
penetration also spread less efficiently through close contact with dried
virus on clothes or other materials. Despite the severity of
Loss of Nucleus the disease and its tendency to spread, several factors con-
outer membrane tributed to its elimination, as listed in Box 44.3. 

Core Uncoating of DNA replication Clinical Syndromes
core, releasing (2-5 hours)
The diseases associated with poxviruses are listed in
viral DNA Table 44.1.

Early transcriptionUncoatase DNA polymerase Late transcription SMALLPOX
Early mRNA The two variants of smallpox disease were variola major,
Late mRNA which was associated with a mortality rate of 15% to 40%,
Early enzymes and variola minor, which was associated with a mortality
Late enzymes rate of 1%. Smallpox was usually initiated by infection of
؉ ؉ the respiratory tract, with subsequent involvement of local
Early virion proteins lymph glands, which in turn led to viremia.
Late virion proteins
The symptoms and course of the disease are presented in
Morphogenesis Spherical immature Fig. 44.3, and the characteristic rash is shown in Fig. 44.4.
After a 5- to 17-day incubation period, the infected person
(4-20 hours) particles experienced high fever, fatigue, severe headache, backache,
and malaise, followed by the vesicular rash in the mouth
Release by cell
disruption BOX 44.2  Disease Mechanisms of Poxvirus

or exocytosis Smallpox is initiated by respiratory tract infection and is spread
mainly by the lymphatic system and cell-associated viremia.
Fig. 44.2  Replication of vaccinia virus. The core is released into the
cytoplasm, where virion enzymes initiate transcription of early genes. Molluscum contagiosum and other poxviruses are transmitted
A viral-encoded “uncoatase” enzyme then causes the release of DNA. by contact.
Viral polymerase replicates the genome, and late transcription occurs.
DNA and protein are assembled into cores within the core membrane. Virus may cause initial stimulation of cell growth and then cell
An outer membrane shrouds the core containing the lateral bodies lysis.
and the enzymes required for infectivity. The virion is exocytosed or is
released by cell lysis. Virus encodes immune evasion mechanisms.
Cell-mediated immunity and humoral immunity are important for
Hemorrhage
of small resolution.
vessels of Most poxviruses share antigenic determinants, allowing prepara-
dermis,
leading to tion of “safe” live vaccines from animal poxviruses.
rash and
“pox” BOX 44.3  Properties of Natural Smallpox
That Led to Its Eradication
Primary viremia Secondary
viremia Viral Characteristics
Multiplication (blood) Exclusive human host range (no animal reservoirs or vectors)
Single serotype (immunization protected against all infections)
Virus Inhalation or in upper Lymphatics Lymph Shares antigenic determinants with other pox viruses. 
transmission respiratory (macrophages) nodes Disease Characteristics
tract Consistent disease presentation with visible pustules (identifica-
by scabs (less
tion of sources of contagion allowed quarantine and vaccina-
effective) tion of contacts) 
Vaccine
Spleen Immunization with animal poxviruses protects against smallpox
Liver Stable, inexpensive, and easy-to-administer vaccine
Bone marrow Presence of scar, indicating successful vaccination 
Additional Public Health Service
Successful worldwide World Health Organization program com-
lymph nodes bining vaccination and quarantine

Organs

Day Prodrome Day Fever, rash Day Pustules

0 12 16

Fig. 44.3  Spread of smallpox within the body. The virus enters and
replicates in the respiratory tract without causing symptoms. The virus
infects macrophages, which enter the lymphatic system and carry the
virus to regional lymph nodes. The virus then replicates and initiates a
viremia, causing the infection to spread to the spleen, bone marrow,
lymph nodes, liver, and all organs, followed by the skin (rash). A sec-
ondary viremia causes the development of additional lesions through-
out the host, followed by death or recovery with or without sequelae.
Recovery from smallpox was associated with prolonged immunity and
lifelong protection.

44  •  Poxviruses 453

TABLE 44.1  Diseases Associated with Poxviruses

Virus Disease Source Location
Humans Extinct
Variola Smallpox (now extinct) Laboratory product —
Vaccinia Used for smallpox vaccination Zoonosis: sheep, goats Worldwide
Zoonosis: rodents, cats, cows Europe
Orf Localized lesion Zoonosis: dairy cows Worldwide
Zoonosis: monkeys, squirrels Africa
Cowpox Localized lesion Zoonosis: calves, beef cattle Worldwide
Rare zoonosis: monkeys Africa
Pseudocowpox Milker nodule Rare zoonosis: monkeys, baboons Africa
Humans Worldwide
Monkeypox Generalized disease

Bovine papular stomatitis virus Localized lesion

Tanapox Localized lesion

Yabapox Localized lesion

Molluscum contagiosum Many skin lesions

Modified from Balows, A., Hausler, W.J., Lennette, E.H. (Eds.), 1988. Laboratory Diagnosis of Infectious Diseases: Principles and Practice, vol. 2. Springer-Verlag, New
York, NY.

Fig. 44.4  Child with smallpox. Note the characteristic rash. Clinical Case 44.1  Vaccinia Infection
in Vaccinated Contacts
and soon after on the body. Vomiting, diarrhea, and exces-
sive bleeding would quickly follow. The simultaneous out- The Centers for Disease Control and Prevention (CDC)
break of the vesicular rash distinguishes smallpox from the (MMWR 56:417–419, 2007) described the case of a
vesicles of varicella-zoster, which erupt in successive crops. woman who visited the public health clinic in Alaska
because the pain from vaginal tears had increased over the
Smallpox was the first disease to be controlled by immu- course of 10 days. There was no fever, itching, or dysuria.
nization, and its eradication is one of the greatest triumphs Clinical examination showed two shallow ulcers, redness,
of public health. Eradication resulted from a massive WHO and vaginal discharge. There was no inguinal lymphad-
campaign to vaccinate all susceptible people, especially enopathy. A viral specimen from the lesion was identified
those exposed to anyone with the disease, interrupting the by the CDC as the vaccine strain of vaccinia virus. Presence
chain of human-to-human transmission. The campaign of the virus was identified by a variation of a polymerase
began in 1967 and succeeded. The last case of naturally chain reaction test, which produces characteristic vaccinia
acquired infection was reported in 1977, and eradication of DNA fragments from the genome. Although the woman
the disease was acknowledged in 1980. routinely insisted on using condoms during sex, a condom
broke during vaginal intercourse with a new male sex
Variolation, an early approach to immunization, partner. The male partner was in the U.S. military and
involved inoculation of susceptible people with the viru- had been vaccinated for smallpox 3 days before initiating
lent smallpox pus. It was first performed in the Far East and his relationship with the woman. Virus from the lesion
later in England. Cotton Mather introduced the practice to was placed on the condom or into the site. Military and
America. Variolation was associated with a fatality rate of other personnel are receiving vaccinia immunization for
approximately 1%, which is a better risk than that associ- protection against weaponized smallpox. This increases
ated with smallpox itself. In 1796, Jenner developed and the potential for unintentional transmission of the vaccinia
then popularized a vaccine using the less virulent cowpox vaccine virus. Other cases of vaccine-related vaccinia
virus, which shares antigenic determinants with smallpox. infection have included infants and individuals with atopic
dermatitis, who had more severe consequences.
Renewed interest is being paid to antiviral drugs that
are effective against smallpox and other poxviruses. Cido- poxvirus infections. Newer, safer vaccines are being stock-
fovir, a nucleotide analog capable of inhibiting the viral piled in response to concerns regarding the use of smallpox
DNA polymerase, is effective and approved for treatment of in biowarfare. 
VACCINIA AND VACCINE-RELATED DISEASE
Vaccinia is the virus used for the smallpox vaccine (Clinical
Case 44.1). Although thought to be derived from cowpox, it
may be a hybrid or other poxvirus. The vaccination proce-
dure consists of scratching live virus into the patient’s skin
with a bifurcated needle and then observing for the devel-
opment of vesicles and pustules to confirm a “take.” As the
incidence of smallpox waned, however, it became apparent
that there were more complications related to vaccination