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544 SECTION 5  •  Virology

Clinical Case 54.1  An Early Case of TABLE 54.5  Indicator Diseases of Acquired
HIV/AIDS Immunodeficiency Syndromea

Elliott and associates (Ann Int Med 98:290–293, 1983) Infection Disease (Selected)
reported that in July 1981, a 27-year-old man complained
of dysuria, fever, chills, night sweats, weakness, dyspnea, OPPORTUNISTIC INFECTIONS
cough with white sputum, anorexia, and a 16-pound
weight loss. For the past 7 years, he had been receiving up Protozoal Toxoplasmosis of the brain
to 4 monthly infusions of factor VIII concentrate to correct Cryptosporidiosis with diarrhea
his hemophilia. He did not have any other risk factors Isosporiasis with diarrhea
for HIV infection. In August, pulmonary infiltrates were
visible by chest radiograph, and in September, blood test Fungal Candidiasis of the esophagus, trachea, and lungs
results were hemoglobin 10.7 g/dL, leukocytes 4200/μL
with 50% polymorphonuclear leukocytes, 2% band forms, Pneumocystis jirovecii pneumonia
36% lymphocytes, and 12% monocytes. Immunoglobulin Cryptococcosis (extrapulmonary)
G antibody was present to cytomegalovirus, Epstein-Barr Histoplasmosis (disseminated)
virus, Toxoplasma, hepatitis B surface antigen, and hepatitis Coccidioidomycosis (disseminated)
B core. An immune deficiency was suggested by a lack of
response in tuberculin, mumps, and Candida skin tests. The Viral Cytomegalovirus disease
presence of Pneumocystis jirovecii in a methenamine silver Herpes simplex virus infection (persistent or dissemi-
stain of a transbronchial lung biopsy specimen prompted nated)
oral treatment with trimethoprim/sulfamethoxazole. Progressive multifocal leukoencephalopathy (JC virus)
Episodes of thrush caused by Candida albicans prompted Hairy leukoplakia caused by Epstein-Barr virus
treatment with ketoconazole. In May of 1982, develop-
ment of splenomegaly and lymphadenopathy prompted ad- Bacterial Mycobacterium avium-intracellulare complex (dissemi-
mission to the hospital, with a leukocyte count of 2100/μL nated)
and only 11% lymphocytes. At this time, Mycobacterium
avium-intracellulare was detected in bone marrow, lymph Any “atypical” mycobacterial disease
nodes, and granulomas, and total lymphocyte counts were Extrapulmonary tuberculosis
448/μL, compared with a normal count of 2668/μL; levels
were not responsive to mitogen stimulation. In July 1982, Salmonella septicemia (recurrent)
total lymphocyte count fell to 220/μL, with 45/μL CD3- Pyogenic bacterial infections (multiple or recurrent)
positive T cells (normal 1725 and 64, respectively) and a
CD4:CD8 ratio of 1:4 (normal 2.2:1). The patient contin- OPPORTUNISTIC NEOPLASIAS
ued to deteriorate and died at the end of September 1982.
Cytomegalovirus was isolated from lung and liver and M. Kaposi sarcoma
avium-intracellulare from most tissue samples. In 1981, Primary lymphoma of the brain
AIDS was a newly described disease, and HIV had not been Hodgkin and non-Hodgkin lymphomas
discovered. Monoclonal antibodies and immunopheno- HPV-associated cancers
typing were new technologies. The patient acquired HIV
infection from the factor VIII concentrate at a time before OTHERS
routine screening of the blood supply.
HIV wasting syndrome
significant diseases, including HIV wasting syndrome HIV encephalopathy
(weight loss and diarrhea for >1 month) and opportunistic Lymphoid interstitial pneumonia
infections, malignancies, and dementia (see Table 54.5).
aManifestations of HIV infection—defining AIDS according to criteria of
AIDS may be manifested in several different ways, includ- Centers for Disease Control and Prevention.
ing lymphadenopathy and fever, opportunistic infections,
malignancies, and AIDS-related dementia. Modified from Belshe, R.B., Textbook of Human Virology, second ed. Mosby,
Lymphadenopathy and Fever St Louis, MO.
Lymphadenopathy and fever develop insidiously and may
be accompanied by weight loss and malaise. These findings HPV, Human papillomavirus.
may persist indefinitely or progress. Symptoms may also
include opportunistic infections, diarrhea, night sweats, BOX 54.4  Clinical Summary
and fatigue. The wasting disease is termed slim disease in
Africa.  A 32-year-old former heroin addict had a mononucleosis-like
Opportunistic Infections illness for 2 weeks. He recalled experiencing occasional night
Normally benign infections caused by agents such as sweats and fever for 3 years and then presented with thrush,
Candida albicans and other fungi, DNA viruses capable cytomegalovirus retinitis, and Pneumocystis pneumonia. His CD4
of recurrent disease, parasites, and intracellularly grow- T-cell count was 50/μL. He was started on highly active antiretro-
ing bacteria cause significant disease after HIV depletion viral therapy.

of CD4 T cells and subsequent reduction of CD8 T cells
(see Table 54.5). Pneumocystis jirovecii–induced
Pneumocystis pneumonia (PCP) is a major sign of
AIDS. Oral candidiasis (thrush), cerebral toxoplasmosis,
and cryptococcal meningitis also often occur, as do pro-
longed and severe viral infections, including molluscum
contagiosum poxvirus, papovaviruses (JC virus, causing
PML), and recurrences of the herpesviruses (e.g., herpes
simplex virus, varicella-zoster virus, EBV [hairy leuko-
plakia of the mouth, EBV-associated lymphomas], cyto-
megalovirus [CMV; especially retinitis, pneumonia, and

54  •  Retroviruses 545

bowel disease], HHV-8 [Kaposi sarcoma]). Tuberculosis TABLE 54.6  Laboratory Analysis for Human
and other mycobacterial diseases and diarrhea caused Immunodeficiency Virus
by common pathogens (Salmonella, Shigella, and Campy-
lobacter species) and uncommon agents (cryptosporidia, Test Purpose
mycobacteria, and Amoeba species) are also common SEROLOGY
problems.   Combined antigen and antibody Initial screening
Malignancies
The most notable malignancy to develop in patients with enzyme-linked immunosorbent Initial screening
AIDS is the HHV-8–associated Kaposi sarcoma, which is a assay Initial screening
rare and otherwise benign skin cancer that disseminates to Initial screening
involve visceral organs in immunodeficient patients. EBV-  Latex agglutination Confirmation testa
related lymphomas are also prevalent.  Detection of virus in blood
Dementia Related to AIDS  Rapid oral antibody test Quantitation of virus in blood
AIDS-related dementia may result from opportunistic infec- Quantitation of virus in blood
tion or HIV infection of the macrophages and microglial  Urine antibody test Early marker of infection
cells of the brain. Patients with this condition may undergo Test not readily available
a slow deterioration of their intellectual abilities and exhibit  Western blot analysis (for antibody) Indicators of HIV disease
other signs of a neurologic disorder, similar to the signs of
the early stages of Alzheimer disease. Neurologic deteriora- Virion RNA RT-PCR
tion could also result from infection with one of the many
opportunistic infections.  Real-time RT-PCR

LABORATORY DIAGNOSIS Branched-chain DNA
Tests for HIV infection are performed for one of four rea-
sons: (1) to identify those with the infection so that anti- p24 antigen
viral drug therapy can be initiated, (2) to identify carriers
who may transmit infection to others (specifically blood Isolation of virus
or organ donors, pregnant women, and sex partners), (3)
to follow the course of disease and confirm the diagno- CD4 T-cell counts, CD4:CD8 T-cell
sis of AIDS, or (4) to evaluate the efficacy of treatment ratio
(Table 54.6).
aWestern blot confirmation is not necessary with fifth-generation combined
The chronic nature of the disease allows the use of sero- p24 antigen and antibody enzyme-linked immunosorbent assay tests.
logic tests to document HIV infection, as supplemented by
genome detection and quantitation with PCR-related tech- RT-PCR, Reverse transcriptase-polymerase chain reaction.
niques. HIV is very difficult to grow in tissue culture, and
virus isolation is not performed. Recent infection or late- in as many as 5% of those infected (see Fig. 54.9). As such,
stage disease are indicated by the presence of large quanti- the new fifth generation screening test is a multiplexed
ties of viral RNA in blood samples, the p24 viral antigen, or enzyme-linked immunosorbent assay (ELISA) that com-
the RT enzyme (see Fig. 54.9). bines detection of the viral p24 antigen, which is present
during the early, acute phase of disease, with detection of
Genomics patient antibody to HIV-1 and HIV-2. Before the combined
Newer methods for detection and quantitation of HIV assays, Western blot analysis of patient serum was neces-
genomes (viral nucleic acid tests [NATs]) in blood have sary to confirm seropositive results. The Western blot assay
become a mainstay for following the course of an HIV (see Fig. 6.6 and Fig. 39.7) demonstrates the presence of
infection and the efficacy and patient compliance with antibody to the viral antigens (p24 or p31) and glyco-
antiviral therapy. After converting viral RNA into DNA proteins (gp41 and gp120/160). In addition to assays for
with an RT (laboratory provided), the cDNA of the genome screening blood, assays of urine, oral mucosal transudate
can be detected by PCR and quantitated by real-time PCR, tests, and rapid screening and home screening tests are also
branched-chain DNA amplification, and other methods available. 
(see Chapter 5). Determination of the viral load (amount Immunologic Studies
of genome in blood) is an excellent indicator of the course The status of an HIV infection can be inferred from an
of disease and efficacy of therapy. These tests are usually analysis of the T-cell subsets. The absolute number of CD4
more expensive than serologic tests and are not used for lymphocytes and the ratio of CD4 to CD8 lymphocytes are
screening.  abnormally low in HIV-infected people. The particular con-
Serology centration of CD4 lymphocytes identifies the stage of AIDS.
Screening of blood and organ donors is performed by serol- The choice to initiate therapy is oftentimes based on CD4
ogy. HIV antibody may develop slowly, taking 4 to 8 weeks T-cell counts. 
in most patients; however, it may take 6 months or more
TREATMENT, PREVENTION, AND CONTROL
The numbers of approved drugs and combinations of anti-
HIV drugs have increased to allow customizing personal
therapy to optimize efficacy and limit adverse effects in an
individual. The principal (as of 2018) anti-HIV therapies
are listed in Box 54.5, but more complete lists are available
on line (see Bibliography). The anti-HIV drugs approved
by the U.S. Food and Drug Administration are classified by
their mechanism of action.

546 SECTION 5  •  Virology

BOX 54.5  Potential Antiviral Therapies for and resulting virion are inactive. Most anti-HIV drugs have
Human Immunodeficiency Virus Infection significant side effects, and the search continues for new
anti-HIV drugs. Each of the replicative steps and all of the
Nucleoside Analog Reverse Transcriptase Inhibitors viral proteins are being targeted for development of new
anti-HIV drugs.
Azidothymidine (AZT) (Zidovudine) [Retrovir]
3TC (Lamivudine) [Epivir] AZT was the first successful anti-HIV therapy. Although
Tenofovir disoproxil fumarate (adenosine class) [Viread] still given to infants born to HIV-positive mothers for 6
ABC (Abacavir) [Ziagen] weeks postpartum, the single use of AZT or another nucleo-
FTC (Emtricitabine) [Emtriva]  tide analog by itself is decreasing. Anti-HIV therapy is cur-
rently given as a cocktail of several antiviral drugs termed
Nonnucleoside Reverse Transcriptase Inhibitors highly active antiretroviral treatment (HAART) (see
Box 54.5). Use of a mixture of drugs with different mecha-
Nevirapine [Viramune] nisms of action has less potential to encounter or select for
Doravirine [Pifeltro] resistance. Multidrug therapy can reduce blood levels of
Efavirenz [Sustiva] virus to nearly zero and reduce morbidity and mortality
Etravirine [Intelence] in many patients with advanced AIDS. Customization of
Rilpivirine [Edurant]  HAART for each patient can minimize the drug side effects,
ease the pill-taking regimen, and allow the patient to return
Protease Inhibitors (PIs) to nearly normal health and lifestyle. Some HAARTs are
taken once a day as a single pill, assisting compliance. Ther-
Tipranavir [Aptivus] apy should be initiated for individuals showing symptoms
Darunavir [Prezista] of AIDS, AIDS-defining illnesses, or if CD4 T cells drop to
Ritonavir [Norvir] less than 350/μL. Therapy may also be considered if viral
Fosamprenavir [Lexiva] loads are high (>100,000), even if CD4 numbers are above
Atazanavir [Reyataz] 350/μL.
Saquinavir [Invirase] 
Preexposure prophylaxis, or PrEP, has recently been
Binding and Fusion Inhibitors approved for people who have a high risk of HIV infec-
tion (e.g., partners of HIV-infected individuals and IV drug
CCR5 inhibitor (maraviroc) [Selzentry] users). Currently, the suggested therapy is a single pill of a
Fusion inhibitor (enfuvirtide) [Fuzeon]  HAART that combines tenofovir and emtricitabine. This
therapy is also appropriate for postexposure prophylaxis
Integrase Inhibitor (e.g., needlestick).

Raltegravir [Isentress] Effective treatment can reduce HIV to undetectable lev-
Dolutegravir [Tivicay]  els, which almost eliminates the risk of transmission. Even
in the absence of a vaccine, combination of proper precau-
Examples of Highly Active Antiretroviral Therapy tions, continued and effective treatment of HIV-infected
individuals, and the administration of PrEP to high-risk
Efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) [Atripla] individuals will significantly reduce the number of HIV
Abacavir/zidovudine/lamivudine [Trizivir] infections in the United States in the near future.
Dolutegravir/abacavir/lamivudine [Triumeq]
Emtricitabine, rilpivirine, and tenofovir disoproxil fumarate [Com- Education
The principal way HIV infection can be prevented and its
plera] spread controlled is by educating the population about
Elvitegravir/cobicistat/tenofovir/emtricitabine [Stribild] the methods of transmission and the measures that may
Emtricitabine/tenofovir disoproxil fumarate [Truvada] curtail viral spread. For instance, monogamous rela-
Lamivudine/zidovudine [Combivir] tionships, the practice of safe sex, and use of condoms
Lopinavir/ritonavir [Kaletra] reduce the possibility of exposure. Because contaminated
needles are a major source of HIV infection in IV drug
Modified from U.S. Department of Health and Human Services, 2018. abusers, people must be taught that needles must not be
FDA-approved HIV medicines. https://aidsinfo.nih.gov/understanding- shared. The reuse of contaminated needles in clinics was
hiv-aids/fact-sheets/21/58/fda-approved-hiv-medicines the source of outbreaks of AIDS in the former Soviet bloc
(accessed 13.09.2018). and other countries. In some places, efforts have been
launched to provide sterile equipment to IV drug abusers.
Inhibition of binding to the CCR5 co-receptor with a A successful anti-HIV education campaign in Uganda
receptor agonist (e.g., maraviroc) or fusion of the viral enve- has been cited as being more effective than antiviral
lope and cell membrane with a peptide (e.g., enfuvirtide) drugs for saving lives. 
that blocks the action of the gp41 molecule will prevent Blood, Blood Product, and Organ Screening
the initial infection event. Inhibition of the integrase (e.g., Potential blood and organ donors are screened before they
dolutegravir, raltegravir) prevents all subsequent events in donate blood, tissue, and blood products. People testing
the replication of the virus. Inhibition of the RT prevents the positive for HIV must not donate blood. People who antici-
initiation of virus replication by blocking cDNA synthesis. pate a future need for blood, such as those awaiting elective
Azidothymidine (AZT) and the other nucleotide analogs are
phosphorylated by cellular enzymes and incorporated into
cDNA by the RT to cause DNA chain termination. Nonnu-
cleoside RT inhibitors (e.g., nevirapine) inhibit the enzyme
by other mechanisms. Protease inhibitors (e.g., darunavir)
block the morphogenesis of the virion by inhibiting cleav-
age of the Gag and Gag-Pol polyproteins. The viral proteins

54  •  Retroviruses 547

surgery, should consider donating blood beforehand. To TABLE 54.7  Mechanisms of Retrovirus Oncogenesis
limit the worldwide epidemic, blood screening must be initi-
ated in developing nations as well.  Disease Speed Effect
Infection Control
The infection-control procedures for HIV infection are Acute Fast: Direct effect
the same as those for hepatitis B virus. They include use leukemia or oncogene Provision of growth-enhancing
of universal blood and body fluid precautions, which are sarcoma
based on the assumption that all patients are infectious Slow: trans- proteins
for HIV and other blood-borne pathogens. Precautions Leukemia activation
include wearing protective clothing (e.g., gloves, mask, Indirect effect
gown) and using other barriers to prevent exposure to Transactivation protein (Tax) or
blood products. Syringes and surgical instruments should
never be reused unless carefully disinfected. Contami- long terminal repeat promoter
nated surfaces should be disinfected with 10% household sequences that enhance expres-
bleach, 70% ethanol or isopropanol, 2% glutaraldehyde, sion of cellular growth genes
and 4% formaldehyde, or 6% hydrogen peroxide. Wash-
ing laundry in hot water with detergent should be suffi- TABLE 54.8  Representative Examples of Oncogenes
cient to inactivate HIV.
Function Oncogene Virus
Circumcision of males reduces their risk of infection.
Circumcision eliminates a site of frequent infections and a Tyrosine kinase Src Rous sarcoma virus
unique microbiome that can cause breaks in the skin and Abl Abelson murine leukemia virus
inflammation, both of which may increase susceptibility to Fes ST feline sarcoma virus
HIV infection. 
Approaches to Vaccine Prophylaxis Growth factor Erb-B (EGF Avian erythroblastosis virus
There are many difficulties in development of a vaccine receptors receptor) Avian erythroblastosis virus
against HIV. A successful vaccine must be able to block the
initial infection and the movement of infected dendritic cells Erb-A (thyroid
and T cells to lymph nodes. Otherwise, like herpesviruses, hormone
HIV infection rapidly establishes a chronic or latent infec- receptor)
tion. The vaccine must elicit neutralizing antibody and cell-
mediated immunity. A major difficulty is that the primary Guanosine triphos- Ha-ras Harvey murine sarcoma virus
target of neutralizing antibody, the gp120, is different for phate–binding Kirsten murine sarcoma virus
the different HIV clades, even within a clade, there are Ki-ras
many antigenically distinct mutants and the virus mutates proteins
extensively creating different strains during the infection
of the individual. Cell-mediated immunity is necessary Nuclear proteins Myc Avian myelocytomatosis virus
because the virus can be spread through cell-to-cell bridges Myb Avian myeloblastosis virus
and remains latent, hiding from antibody. Finally, test- Fos Murine osteosarcoma virus FBJ
ing of the vaccine is difficult and expensive because large Jun Avian sarcoma virus 17
numbers of susceptible people must be evaluated, and long-
term follow-up is required to monitor the efficacy of each EGF, Epidermal growth factor; FBJ, Finkel-Biskis-Jinkins; ST, Snyder-Theilen.
formulation.
Human T-Cell Lymphotropic
Several different approaches have been tried for devel- Virus and Other Oncogenic
oping an HIV vaccine. Live attenuated vaccines (e.g., dele- Retroviruses
tion of the nef gene) were too dangerous because they still
caused disease in infants and may establish chronic infec- The Oncovirinae were originally called the RNA tumor
tion. Protein subunit vaccines with gp120 or its precursor, viruses and have been associated with the development
gp160, by themselves, elicit only antibody to a single strain of leukemias, sarcomas, and lymphomas in many animals.
of HIV and have not been successful. The stem region of These viruses are not cytolytic. Members of this family are
the gp120 does not differ extensively between strains and distinguished by their mechanism of cell transformation
vaccines that expose this region elicit antibody to multiple (immortalization) and thus the length of the latency period
strains. Immunization with hybrid HIV vaccines that incor- between infection and development of disease (Table 54.7).
porate the gene for gp160 (env) and other HIV genes into a
vaccinia, canarypox, or defective adenovirus vector or into The sarcoma and acute leukemia viruses have
a DNA or RNA vaccine can initiate cell-mediated responses. incorporated modified versions of cellular genes (protoon-
This can be followed by a protein boost with gp120 or cogenes) encoding growth-controlling factors into their
gp160 to activate B cells and develop neutralizing antibody. genome (v-onc). These include genes that encode growth
The gp120 and gp160 proteins are genetically engineered hormones, growth hormone receptors, protein kinases,
and expressed in different eukaryotic cell systems (e.g., guanosine triphosphate–binding proteins (G-proteins), and
yeast, baculovirus).  nuclear DNA–binding proteins. These viruses can cause
transformation of cells relatively rapidly and are highly
oncogenic. No human virus of this type has been identified.

At least 35 different viral oncogenes have been identified
(Table 54.8). Transformation results from the overproduc-
tion or altered activity of the growth-stimulating protein
encoded by the oncogene. Increased cell growth then pro-
motes transcription, which also promotes viral replication.

548 SECTION 5  •  Virology

Incorporation of the oncogene into many of these viruses at birth and in breast milk from their mothers, whereas
causes the coding sequences for the gag, pol, or env genes adults are infected sexually. The number of seropositive
to be replaced, such that most of these viruses are defective people in some regions of Japan may be as high as 35%
and require helper viruses for replication. Many of these (Okinawa), and 40% in some regions of Australia. The
viruses become endogenous and then are transmitted verti- mortality rate from leukemia may be twice that of other
cally through the germline of the animal. regions. IV drug abuse and blood transfusion are becom-
ing the most prominent means of transmitting the virus
The human oncoviruses include HTLV-1, HTLV-2, and in the United States, in which the high-risk groups for
HTLV-5, but only HTLV-1 has been definitively associated HTLV-1 infection are the same as those for HIV infection.
with disease (i.e., adult T-cell leukemia [ATLL]). HTLV-2
was isolated from atypical forms of hairy cell leukemia, HTLV-2 is endemic in many native Amerindian groups.
and HTLV-5 was isolated from a malignant cutaneous IV drug users are at high risk for infection. 
lymphoma. HTLV-1 and HTLV-2 share as much as 50%
homology. The leukemia viruses, including HTLV-1, are CLINICAL SYNDROMES
competent in terms of replication but cannot transform cells HTLV infection is usually asymptomatic but can progress
in vitro. They cause cancer after a long latency period of to ATLL in approximately 1 in 20 persons over a 30- to
at least 30 years. The leukemia viruses promote cell growth 50-year period. ATLL caused by HTLV-1 is a neoplasia of the
in more indirect ways than the oncogene-encoding viruses. CD4 helper T cells that can be acute or chronic. The malig-
HTLV-1 also causes HTLV-1–associated myelopathy (HAM) nant cells have been termed “flower cells” because they are
(tropical spastic paraparesis), which is a nononcogenic pleomorphic and contain lobulated nuclei. In addition to an
neurologic disease. elevated white blood cell count, this form of ATLL is char-
acterized by skin lesions similar to those seen in another
PATHOGENESIS AND IMMUNITY leukemia, Sézary syndrome. ATLL is usually fatal within a
HTLV-1 is cell associated and is spread in cells after blood year of diagnosis, regardless of treatment. HTLV-1 can also
transfusion, sexual intercourse, or breastfeeding. The virus cause other diseases, including HAM (tropical spastic para-
enters the bloodstream and infects the CD4 helper T cells. In paresis), uveitis, HTLV-associated infectious dermatitis, and
addition to blood and lymphatic organs, these T cells have a other inflammatory disorders. HAM can lead to demyelin-
tendency to reside in the skin, contributing to the symptoms ation of the spinal cord and paralysis. HTLV infection is also
of ATLL. Neurons also express a receptor for HTLV-1. immunosuppressive. HTLV-2 infection is unlikely to cause
leukemia but may cause neurologic disease, such as HAM. 
The PX gene of HTLV-1 encodes additional proteins (tax,
rex, p12, p13, p30, and HBZ) that promote cell growth, LABORATORY DIAGNOSIS
cause evasion of immune detection, and facilitate leuke- HTLV-1 infection is detected using ELISA to find virus-
mogenic transformation. Tax is a transcriptional regulator specific antigens in blood, using RT-PCR for viral RNA, or
that can activate promoters in the viral LTR gene region using ELISA to detect specific antiviral antibodies. 
and specific cellular genes (including growth-controlling
and cytokine genes, such as those encoding IL-2, IL-2 TREATMENT, PREVENTION, AND CONTROL
receptor, and granulocyte-macrophage colony-stimulat- A combination of AZT and interferon (IFN)-α has been
ing factor) to promote the outgrowth of that cell. The virus effective in some patients with ATLL. However, no partic-
also encodes HBZ to limit Tax activity and promote cell pro- ular treatment has been approved for the management of
liferation and viral persistence. HBZ and tax are important HTLV-1 infection.
for promoting leukemogenesis. HTLV-1 can also stimulate
growth of the cell by integrating near cellular growth-con- The measures used to limit the spread of HTLV-1 are
trolling genes to allow the enhancer and promoter gene the same as those used to limit the transmission of HIV.
sequences encoded in the viral LTR region to promote the Sexual precautions, screening of the blood supply, and
expression of the cellular growth-stimulating proteins. increased awareness of the potential risks and diseases
Other genetic changes required to produce leukemia are are ways to prevent transmission of the virus. Routine
more likely to occur because of the stimulated growth of screening for HTLV-1, HIV, hepatitis B virus, and hep-
the infected cell. atitis C virus is performed to protect the blood supply.
Maternal infection of children is very difficult to control,
There is a long latency period (≈30 years) before the however. 
onset of leukemia. Although the virus can induce a poly-
clonal outgrowth of T cells, HTLV-1–induced ATLL is usu- Endogenous Retroviruses
ally monoclonal.
Different retroviruses have integrated into and become a part
Antibodies are elicited to the gp46 and other proteins of of the chromosomes of humans and animals. In fact, ret-
HTLV-1. HTLV-1 infection also causes immunosuppression.  rovirus sequences may make up at least 8% of the human
genome. Complete and partial provirus sequences with gene
EPIDEMIOLOGY sequences similar to those of HTLV, mouse mammary tumor
HTLV-1 is transmitted and acquired by the same routes virus, and other retroviruses, can be detected in humans.
as HIV. It is endemic in southern Japan, Australia, the
Caribbean, Central Africa, and among African Ameri-
cans in the southeastern United States. In the endemic
regions of Japan and Australia, children acquire HTLV-1

54  •  Retroviruses 549

These human endogenous retroviruses (HERVs) gener- HIV/AIDS and HTLV Websites
ally lack the ability to replicate because of deletions or the About.com: AIDS/HIV. http://aids.about.com/. Accessed September 11,
insertion of termination codons, or because they are poorly
transcribed. In addition, our cells express proteins, such as 2018.
apolipoprotein B editing catalytic (APOBEC) proteins, to sup- Avert: Global information and education on HIV and AIDS.
press the replication of endogenous retroviruses. One such
retrovirus can be detected in placental tissue and is activated https://www.avert.org/public-hub. Accessed September 11, 2018
by pregnancy. This virus produces syncytin, which is neces- Bennett, N.J., HIV disease. http://emedicine.medscape.com/arti
sary to facilitate placental function. Other HERVs are associ-
ated with prostate and other cancers, multiple sclerosis, and cle/211316-overview. Accessed September 11, 2018.
amyotrophic lateral sclerosis (ALS). Centers for Disease Control and Prevention: HIV/AIDS statistics and sur-

  For a case study and questions see StudentC­ onsult.com veillance. www.cdc.gov/hiv/library/reports/surveillance/index.html.
Accessed September 11, 2018.
Bibliography National Institutes of Health: http://aidsinfo.nih.gov/. Accessed Septem-
ber 11, 2018
Cohen, J., Powderly, W.G., 2004. Infectious Diseases, second ed. Mosby, Szczypinska, E.M., Wallace, M.R., Wainscoat, B., et al., Human T-cell lym-
St Louis. photropic viruses. http://emedicine.medscape.com/article/219285-
overview. Accessed September 11, 2018.
Doltch, G., Cavrois, M., Lassen, K.G., et al., 2010. Abortive HIV infection UNAIDS, Homepage. www.unaids.org/. Accessed 11 September 2018.
mediates CD4 T cell depletion and inflammation in human lymphoid tis- University of California, San Francisco: HIV InSite. http://hivinsite.ucsf.
sue. Cell 143, 789–801. edu. Accessed September 11, 2018.
U.S. Department of Health and Human Services: Clinical guidelines portal:
Flint, S.J., Racaniello, V.R., et al., 2015. Principles of Virology, fourth ed. federally approved HIV/AIDS medical practice guidelines. http://aidsinf
American Society for Microbiology Press, Washington, DC. o.nih.gov/guidelines. Accessed September 11, 2018.

Kannian, P., Green, P.L., 2010. Human T lymphotropic virus type 1 HIV Exposure and Therapy Websites
(HTLV-1): molecular biology and oncogenesis. Viruses. 2 (9), 2037– Centers for Disease Control and Prevention: Updated U.S. Public Health
2077. https://doi.org/10.3390/v2092037.
Service guidelines for the management of exposures to HIV and recom-
Knipe, D.M., Howley, P.M., 2013. Fields Virology, sixth ed. Lippincott Wil- mendations for postexposure prophylaxis. https://stacks.cdc.gov/view/
liams & Wilkins, Philadelphia. cdc/20711. Accessed September 11, 2018.
Federal Drug Administration. https://www.fda.gov/ForPatients/Illness/
Kräusslich, H.G., 1996. Morphogenesis and Maturation of Retroviruses. HIVAIDS/Treatment/ucm118915.htm. Accessed September 8, 2018.
Springer-Verlag, Berlin. National Institutes of Health. https://aidsinfo.nih.gov/understanding-hiv-
aids/fact-sheets/21/58/fda-approved-hiv-medicines. Accessed Septem-
Levy, J.A., 2007. HIV and the Pathogenesis of AIDS, seventh ed. American ber 8, 2018.
Society for Microbiology Press, Washington, DC. National Institutes of Health. Drugs. https://aidsinfo.nih.gov/drugs.
Accessed September 11, 2018.
Morse, S.A., Holmes, K.K., et al., 2011. Atlas of Sexually Transmitted Dis- Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines
eases and AIDS, fourth ed. Saunders, St Louis. for the use of antiretroviral agents in HIV-1–infected adults and adoles-
cents. Department of Health and Human Services. https://aidsinfo.ni-
Ryan, F.P., 2004. Human endogenous retroviruses in health and disease: h.gov/guidelines/html/1/adult-and-adolescent-arv/2/introduction.
a symbiotic perspective. J. R. Soc. Med. 97, 560–565. Accessed September 11, 2018.

Stine, G.J., 2011. AIDS Update 2011. McGraw-Hill, New York.
Strauss, J.M., Strauss, E.G., 2007. Viruses and Human Disease, second ed.

Academic, San Diego.

Case Study and Questions 4. What precautions should be taken in handling samples
from this patient?
A 28-year-old man had several complaints. He had a bad
case of thrush (oral candidiasis) and low-grade fever, had 5. What precautions could the patient have taken to pre-
serious bouts of diarrhea, had lost 20 pounds in the past vent infection?
year without dieting, and most seriously, he complained of
difficulty breathing. His lungs showed a bilateral infiltrate 6. Several forms of HIV vaccines are being developed. What
on radiographic examination, characteristic of P. jirovecii are possible components of an HIV vaccine? Who would
pneumonia. A stool sample was positive for Giardia organ- be appropriate recipients of an HIV vaccine?
isms. He was a heroin addict and admitted to sharing nee- Thought Question: HERVs are the ultimate passen-
dles at a shooting gallery.
1. What laboratory tests could be done to support and con- gers in our cells. Infections with EBV or CMV can activate
one of the HERVs; infections with other retroviruses (HTLV
firm a diagnosis of HIV infection and AIDS? or HIV) or other stimuli may activate other HERVs. Con-
2. How did this man acquire the HIV infection? What are sider their possible influence on the functioning and physi-
ology of our cells, immune system, and other functions. (See
other high-risk behaviors for HIV infection? review by Ryan [J R Soc Med 2004;97:560–565] for some
3. What was the immunologic basis for the increased sus- answers.)

ceptibility of this patient to opportunistic infections?

549.e1

55 Hepatitis Viruses

A 43-year-old woman complained of fatigue, nausea, A 41-year-old intravenous drug abuser complained
and abdominal discomfort. She had a slight fever, her of fatigue, nausea, and abdominal discomfort. He
urine was dark yellow, and her abdomen was dis- had a slight fever, his urine was dark yellow, and his
tended and tender. Serologic assays demonstrated abdomen was distended and tender. Serologic assays
the presence of immunoglobulin (Ig)M antibody to demonstrated the presence of IgG antibody to the
the hepatitis B core antigen (HBcAg) and the pres- HBsAg but no hepatitis antigens or other anti-HBV
ence of the hepatitis B surface antigen (HBsAg) and antibodies. Reverse transcriptase-polymerase chain
the hepatitis Be antigen (HBeAg). She also had IgG to reaction (RT-PCR) analysis of his serum detected the
hepatitis A virus. hepatitis C virus (HCV) genome.
1. Which aspects are common to hepatitis disease and 5. Is this person infected with HBV? Has this person ever

which are specific to hepatitis B virus (HBV)? been infected with HBV?
2. How does serology define the course of this disease? 6 . What is the most likely disease outcome for this patient?
3. How is this infection transmitted?
4. H ow could this infection and disease be prevented? Other patients with this infection?
7 . How can this infection be treated?
How could it be treated?
  Answers to these questions are available on Student
Consult.com.

Summaries Clinically Significant Organisms

HEPATITIS VIRUSES ᑏᑏ Hepatitis A: nonlytic picornavirus, acute Epidemiology
onset, no sequelae
Trigger Words ᑏᑏ HAV, HEV: fecal-oral transmission
ᑏᑏ Hepatitis B: hepadnavirus, enveloped ᑏᑏ HBV, HCV, HDV: spread in blood, tissue,
Hepatitis A: acute/sudden onset, picorna- and encodes reverse transcriptase
virus, fecal-oral ᑏᑏ Disease followed by serology and semen; STDs
ᑏᑏ Chronic disease 5% of time, especially
Hepatitis B: blood-borne, STD, hepadnavi- in children Diagnosis
rus, reverse transcriptase, chronic, Dane ᑏᑏ Risk for PHC
particle, HBsAg ᑏᑏ RT-PCR, ELISA
ᑏᑏ Hepatitis C: flavivirus
Hepatitis C: chronic, blood-borne, flavivirus ᑏᑏ Causes chronic disease in 70% of Treatment, Prevention, and Control
Hepatitis D: defective, hepatitis B helper patients
ᑏᑏ Risk for PHC and cirrhosis after long ᑏᑏ HAV: inactivated vaccine, hygiene
virus, fulminant disease period ᑏᑏ HEV: hygiene
Hepatitis E: fecal-oral, acute/sudden onset, ᑏᑏ HBV: virus-like particle HBsAg vaccine,
ᑏᑏ Hepatitis D: viroid-like, requires HBV as
pregnant women helper virus screening of blood supply, safe sex,
antiviral drugs
Biology, Virulence, and Disease ᑏᑏ Hepatitis E: Hepevirus, calici-like virus, ᑏᑏ HCV: screening of blood supply, safe sex,
acute onset, no sequelae, severe for antiviral drugs
ᑏᑏ Liver disease defines symptoms pregnant women ᑏᑏ HDV: immunization for HBV
ᑏᑏ Nonlytic viruses: cell-mediated immunity

causes symptoms

ELISA, Enzyme-linked immunosorbent assay; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis
D virus; HEV, hepatitis E virus; PHC, primary hepatocellular carcinoma; RT-PCR, reverse transcriptase-polymer chain reaction; STD, sexually transmitted disease.

The hepatitis alphabet of viruses includes at least six viruses, liver enzymes. The specific virus causing the disease can
A through E and G (Table 55.1; a summary is provided in Box be distinguished by the course, nature, and serology of the
55.1). Although the target organ for each of these viruses is disease. These viruses are readily spread because infected
the liver and the basic hepatitis symptoms are similar, they people are contagious before, or even without showing
differ greatly in their structure, mode of replication, mode symptoms.
of transmission, and in the time course and sequelae of the
disease they cause. Hepatitis A and hepatitis B viruses Hepatitis A, which is sometimes known as infectious
(HAV, HBV) are the classic hepatitis viruses, and hepatitis hepatitis, is caused by a picornavirus, which is a ribonu-
C, D, E, and G viruses (HCV, HDV [the delta agent], HEV, cleic acid (RNA) virus. It is spread by the fecal-oral route,
and HGV) are called non-A, non-B hepatitis (NANBH) has an incubation period of approximately 1 month, after
viruses. Other viruses can also cause hepatitis. which icteric symptoms start abruptly, does not cause chronic
liver disease, and rarely causes fatal disease.
Each of the hepatitis viruses infects and initiates inflam-
matory responses that damage the liver, causing the clas- Hepatitis B, previously known as serum hepatitis,
sic icteric symptoms of jaundice and the release of is caused by a hepadnavirus with a deoxyribonucleic acid
550 (DNA) genome; is spread parenterally by blood or needles,

55  •  Hepatitis Viruses 551

by sexual contact, and perinatally; has a median incuba- BOX 55.1  Everything You Want to Know
tion period of approximately 3 months, after which icteric About Hepatitis Viruses a la Dr. Seuss
symptoms start insidiously; is followed by chronic hepatitis
in 5% to 10% of patients; and is causally associated with Hepatitis A, B, C
primary hepatocellular carcinoma (PHC). More than one- Hepatitis D, E, G
third of the world’s population has been infected with HBV, Liver is the target
resulting in 1 to 2 million deaths per year. The incidence of But immune response hurts me
HBV is decreasing, however, especially in infants, because Liver suffers from A to G
of the development and use of the HBV subunit vaccine.
Eat the virus, it won’t stay
HCV is caused by a flavivirus with an RNA genome, is E and A go away
spread by the same routes as HBV with more than 170 Poop, water, and shellfish dot dot A
million chronically infected carriers of the disease, is more That’s the acute virus that goes away
likely to cause asymptomatic infection and cause chronic Pregnant woman fears the E
disease than HBV, and increases risk for PHC. It is deadly but not for me

HGV is also a flavivirus and causes chronic infections. B and C and also D
HEV is an enteric, encapsidated virus with an RNA Blood, tissue, and semen can carry the three
genome in its own family, and its disease resembles HAV B and C stay with me
but can be severe in pregnant women. PHC with C and B
Hepatitis D, or delta hepatitis, is unique in that it For the baby, chronic B
requires actively replicating HBV as a “helper virus” and HBsAg you will see
occurs only in patients who have active HBV infection. HBV
provides an envelope for HDV RNA and its antigens. HDV Anti-HBs no more sick
exacerbates the symptoms caused by HBV. Vaccines do this, that’s the trick
Antivirals for B and C
Hepatitis A Virus Immunize for A or B
Risky business A through G
HAV causes infectious hepatitis and is spread by the fecal- Yellow eyes you will see
oral route. HAV infections often result from consumption
by K.S. Rosenthal

HBsAg, Hepatitis B surface antigen; PHC, primary hepatocellular carci-
noma.

TABLE 55.1  Comparative Features of Hepatitis Viruses

Feature Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
Common name “Infectious” “Serum” “Delta agent” “Enteric non-A, non-B”
Picornavirus; “Non-A, non-B
Virus structure Hepadnavirus; envelope, posttransfusion” Viroid-like; envelope, Hepevirus capsid, (+)
capsid, (+) RNA DNA circular RNA RNA
Transmission Fecal-oral Flavivirus; envelope,
Onset Abrupt Parenteral, sexual (+) RNA Parenteral, sexual Fecal-oral
Incubation 15-50 Insidious Abrupt Abrupt
45-160 Parenteral, sexual 15-64 15-50
period (days) Mild
Severity Insidious
<0.5%
Mortality 14-180+
No
Chronicity/ Occasionally severe, Usually subclinical; Co-infection with HBV Normal patients, mild;
carrier state None 3%-10% chronicity 70% chronicity occasionally severe; pregnant women,
in adults; 30%-90% in superinfection with severe
Other disease Symptoms and infants and children ≈4% HBV often severe
associations anti-HAV IgM Normal patients,
1%-2% Yes High to very high 1%-2%; pregnant
Laboratory women, 20%
diagnosis Yes Yes
No

Primary hepatocellular Primary hepatocellular Cirrhosis, fulminant None
carcinoma, cirrhosis carcinoma, cirrhosis hepatitis —

Symptoms, serum Symptoms and Anti-HDV ELISA

levels of HBsAg, HBeAg, anti-HCV ELISA,

and anti-HBc IgM, genome genome testing

ELISA, Enzyme-linked immunosorbent assay; HAV, hepatitis A virus; HBc, hepatitis B core; HBeAg, hepatitis Be antigen; HBsAg, hepatitis B surface antigen; HBV,
hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; IgM, immunoglobulin M.

552 SECTION 5  •  Virology Oral
acquisition
Capsid
ssRNA
(7478 bases)

27 nm

VPg Crosses intestines Blood

Fig. 55.1  Picornavirus structure of hepatitis A virus. The icosahedral Bile
capsid is made up of four viral polypeptides (VP1 to VP4). Inside the
capsid is a single-stranded positive-sense ribonucleic acid (ssRNA) that Stool
has a genomic viral protein (VPg) on the 5′ end.
Fig. 55.2  Spread of hepatitis A virus within the body.
BOX 55.2  Characteristics of Hepatitis A
Virus and continuous monkey kidney cell lines, but clinical iso-
lates are difficult to grow in cell culture. 
Stable to:
Acid at pH 1 PATHOGENESIS
Solvents (ether, chloroform) HAV is ingested and probably enters the bloodstream
Detergents through the epithelial lining of the oropharynx or the intes-
Salt water, groundwater (months) tines to reach its target, which are the parenchymal cells of
Drying (stable) the liver (Fig. 55.2). The virus replicates in hepatocytes and
Kupffer cells. Virus is produced in these cells and is released
Temperature: into the bile and from there into the stool. Virus is shed in
4° C for weeks: stable large quantities into the stool approximately 10 days before
56° C for 30 minutes: stable symptoms of jaundice appear or antibody can be detected.
61° C for 20 minutes: partial inactivation
HAV replicates slowly in the liver without producing
Inactivated by: apparent cytopathic effects. Although interferon limits
Chlorine treatment of drinking water viral replication, natural killer cells and cytotoxic T cells are
Formalin (0.35%, 37° C, 72 hours) required to eliminate infected cells. Antibody, complement,
Peracetic acid (2%, 4 hours) and antibody-dependent cellular cytotoxicity also facilitate
β-Propiolactone (0.25%, 1 hour) clearance of the virus and induction of immunopathology.
Ultraviolet radiation (2 μW/cm2/min) Icterus, resulting from damage to the liver, occurs because
of inflammation of the liver when cell-mediated immune
of contaminated water, shellfish, or other food. HAV is a responses and antibody to the virus can be detected. Anti-
picornavirus and was formerly called enterovirus 72, but it body protection against reinfection is lifelong.
has been placed into its own genus, Hepatovirus.
The liver pathology caused by HAV infection is indistin-
STRUCTURE guishable histologically from that caused by HBV. It is most
HAV has a 27-nm, naked, icosahedral capsid surround- likely caused by immunopathology and not virus-induced
ing a positive-sense single-stranded RNA genome con- cytopathology. However, unlike HBV, HAV cannot initi-
sisting of approximately 7470 nucleotides (Fig. 55.1). As a ate a chronic infection and is not associated with hepatic
picornavirus, the HAV genome has a VPg protein attached cancer. 
to the 5′ end and a polyadenylate sequence attached to the
3′ end. The capsid is even more stable than other picornavi- EPIDEMIOLOGY
ruses to acid and other treatments (Box 55.2). There is only Approximately 40% of acute cases of hepatitis are caused
one serotype of HAV but there are multiple genotypes.  by HAV (Box 55.3). The virus spreads readily in a commu-
nity because most infected people are contagious 10 to 14
REPLICATION days before symptoms occur, and 90% of infected children
HAV replicates like other picornaviruses (see Chapter 46). and 25% to 50% of infected adults have inapparent but
It interacts specifically with the HAV cell receptor 1 glyco- productive infections.
protein (HAVCR-1, which is also known as T-cell immuno-
globulin and mucin domain protein [TIM-1]) expressed on The virus is released into stool in high concentrations and
liver cells and T cells. The structure of HAVCR-1 can vary is spread via the fecal-oral route. Virus is spread in contami-
for different individuals, and specific forms correlate with nated water, in food, and by dirty hands. HAV is resistant to
severity of disease. Unlike other picornaviruses, however, detergents, acid (pH of 1), and temperatures as high as 60°
HAV is not cytolytic and is released by exocytosis. Labora- C, and it can survive for many months in fresh water and
tory isolates of HAV have been adapted to grow in primary salt water. Raw or improperly treated sewage can taint the

55  •  Hepatitis Viruses 553

BOX 55.3  Epidemiology of Hepatitis A Antibody or virus concentration Icteric symptoms (if present)
Virus and Hepatitis E Virus Elevated serum liver enzymes

Disease/Viral Factors Incubation Prodrome
Virus in blood
Capsid viruses are strongly resistant to inactivation.
Contagious period extends from before to after symptoms. Virus detectable in liver biopsy and feces
Virus may cause asymptomatic shedding.  HAV-specific IgG

Transmission Virus in HAV-specific IgM
feces
Virus can be transmitted via fecal-oral route.
Ingestion of contaminated food and water can cause infection. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
HAV in shellfish is from sewage-contaminated water. Weeks
HEV from pigs and game animals.
Virus can be transmitted by food handlers, day-care workers, and Ingestion
of virus
children. 
Fig. 55.3  Time course of hepatitis A virus (HAV) infection. Note that
Who Is at Risk? the person is contagious before onset of symptoms and that symptoms
correlate with the onset of immune responses. Ig, Immunoglobulin.
People in overcrowded, unsanitary areas
Travelers to high-risk regions to the liver. The symptoms occur abruptly 15 to 50
days after exposure, intensify for 4 to 6 days before the
Children: mild disease, possibly asymptomatic; day-care centers icteric (jaundice) phase, and can last for up to 2 months
are a major source of spread of HAV (Fig. 55.3). Initial symptoms include fever, fatigue, nau-
sea, loss of appetite, vomiting, and abdominal pain. The
Adults: abrupt-onset hepatitis icteric phase is indicated by jaundice, dark urine (bilirubi-
Pregnant women: high mortality associated with HEV  nuria), and pale stool and may be accompanied by abdom-
inal pain. As already noted, disease in children is generally
Geography/Season milder than that in adults and is usually asymptomatic.
Jaundice is observed in 70% to 80% of adults but in only
Virus is found worldwide. 10% of children (<6 years of age). Symptoms generally
There is no seasonal incidence.  wane during the jaundice period. Viral shedding in the
stool precedes the onset of symptoms by approximately 14
Means of Control days but stops before the cessation of symptoms. Complete
recovery occurs 99% of the time within 2 to 4 weeks of
Good hygiene. onset.
HAV: passive antibody protection for contacts
Fulminant hepatitis is less likely for HAV infection but
Killed vaccine occurs in 1 to 3 persons per 1000 and is associated with an
Live vaccine in China 80% mortality rate. Unlike HBV, immune complex–related
symptoms (e.g., arthritis, rash) rarely occur in people with
HAV, Hepatitis B virus: HEV, hepatitis E virus. HAV disease. 

water supply and contaminate shellfish. Shellfish, especially LABORATORY DIAGNOSIS
clams, oysters, and mussels, are important sources of the virus The diagnosis of HAV infection is generally made on the
because they are efficient filter feeders and can therefore con- basis of the time course of the clinical symptoms, iden-
centrate the viral particles, even from dilute solutions. This is tification of a known infected source, and most reliably,
exemplified by an epidemic of HAV that occurred in Shanghai, results of specific serologic tests. The best way to demon-
China, in 1988, when 300,000 people were infected with the strate an acute HAV infection is by finding anti-HAV IgM,
virus after eating clams obtained from a sewage-polluted river. as measured by an enzyme-linked immunosorbent assay
(ELISA). Virus isolation is not performed, because effi-
HAV outbreaks usually originate from a common source cient tissue culture systems for growing the virus are not
(e.g., water supply, restaurant, day-care center). Asymp- available. Viral RNA in blood or stool can also be detected
tomatic shedding and a long (15 to 40 days) incubation by reverse transcriptase polymerase chain reaction (RT-
period make it difficult to identify the source. Day-care PCR) or real-time PCR analysis to follow the course of the
settings are a major source for spread of the virus among disease. 
classmates and their parents. Because the children and per-
sonnel in day-care centers may be transient, the number
of contacts at risk for HAV infection from a single day-care
center can be great.

HAV infections are relatively common, with greater inci-
dence with poor hygienic conditions and overcrowding.
Most people infected with HAV in developing countries are
children who have mild illness and then lifelong immune
protection against reinfection. In the United States, the inci-
dence has dropped significantly with use of the vaccine. 

CLINICAL SYNDROMES

The symptoms caused by HAV are very similar to those
caused by HBV and stem from immune-mediated damage

554 SECTION 5  •  Virology

BOX 55.4  Unique Features of L
Hepadnaviruses Hepatitis B surface antigen M
S
Virus has enveloped virion containing partially double-stranded, DNA polymerase
circular DNA genome.
DNA (mostly double-stranded),
Replication is through an overlapping circular RNA intermediate. 3200 bp
Virus encodes and carries a reverse transcriptase.
Virus encodes several proteins (HBsAg [L, M, S]; HBe/HBc antigens) 42 nm Core antigens HBc, HBe
Protein kinase
that share genetic sequences but with different in-frame start
codons. Dane particle
HBV has a strict tissue tropism to the liver.
HBV-infected cells produce and release large amounts of HBsAg 22 nm
particles lacking DNA.
The HBV genome can integrate into the host chromosome. 22 nm

HBc, Hepatitis B core antigen; HBe, hepatitis Be antigen; HBsAg, hepatitis 100-700 nm
B surface antigen; HBV, hepatitis B virus. HBsAg

TREATMENT, PREVENTION, AND CONTROL Fig. 55.4  Hepatitis B virus (Dane particle) and hepatitis B surface
The spread of HAV is reduced by interrupting the fecal-oral antigen (HBsAg) particles. The spherical HBsAg consists mainly of the
spread of the virus. This is accomplished by avoiding poten- S form of HBsAg, with some M. The filamentous HBsAg has S, M, and
tially contaminated water or food, especially uncooked L forms. bp, Base pair; DNA, deoxyribonucleic acid; L, gp42; M, gp36;
shellfish, and by proper processing of sewage. Proper hand- S, gp27.
washing, especially in day-care centers, mental hospitals,
and other care facilities, is vitally important. Chlorine treat- virus. They resist treatment with ether, low pH, freezing, and
ment of drinking water is generally sufficient to kill the virus. moderate heating. These characteristics assist transmission
from one person to another and hamper disinfection.
Prophylaxis with immune serum globulin given
before or early in the incubation period (i.e., <2 weeks after The HBV virion includes a protein kinase and a
exposure) is 80% to 90% effective in preventing clinical illness. polymerase with reverse transcriptase and ribonuclease H
activity, as well as a P protein attached to the genome. All
Killed HAV vaccines are recommended for all chil- of this is surrounded by an icosahedral capsid formed by the
dren after 1 year of age and for adults at high risk for hepatitis B core antigen (HBcAg) and an envelope con-
infection, including travelers to endemic regions, intra- taining three forms of the glycoprotein hepatitis B surface
venous drug abusers, and men who have sex with men. antigen (HBsAg). The hepatitis Be antigen (HBeAg)
The vaccine is administered in two doses, 6 months protein shares most of its protein sequence with HBcAg but
apart, and can be administered with the HBV vaccine. is processed differently by the cell, is primarily secreted into
Live HAV vaccines are in use in China. There is only one serum, does not self-assemble (like the core capsid antigen),
serotype of HAV, and HAV infects only humans; these and expresses different antigenic determinants.
are all factors that help ensure the success of an immuni-
zation program.  HBsAg-containing particles are released into the
serum of infected people and outnumber the actual virions.
Hepatitis B Virus These particles can be spherical (but smaller than the Dane
particle) or filamentous (see Fig. 55.4). They are immuno-
HBV is the major member of the hepadnaviruses. Other genic and were processed into the first commercial vaccine
members of this family (Box 55.4) include woodchuck, against HBV.
ground squirrel, and duck hepatitis viruses. These viruses
have limited tissue tropisms and host ranges. HBV infects HBsAg, originally termed the Australia antigen, includes
the liver and, to a lesser extent, the kidneys and pancreas of three glycoproteins (L, M, and S) encoded by the same gene
humans and chimpanzees. Advances in molecular biology and read in the same frame but translated into protein from
have made it possible to study HBV despite the limited host different AUG (adenine, uracil, guanine) start codons. The
range of the virus and the difficult cell-culture systems in S (gp27; 24 to 27 kDa) glycoprotein is completely contained
which to grow it. in the M (gp36; 33 to 36 kDa) glycoprotein, which is con-
tained in the L (gp42; 39 to 42 kDa) glycoprotein; all share
STRUCTURE
HBV is a small enveloped DNA virus with several unusual
properties (Fig. 55.4). Specifically, the genome is a small,
circular, partly double-stranded DNA of only 3200
bases. Although a DNA virus, it encodes a reverse tran-
scriptase and replicates through an RNA intermediate.

The virion, also called the Dane particle, is 42 nm in
diameter. The virions are unusually stable for an enveloped

55  •  Hepatitis Viruses 555

the same C-terminal amino acid sequences. All three forms The attachment of HBV to hepatocytes is mediated by the
of HBsAg are found in the virion. The S glycoprotein is the HBsAg glycoproteins. The liver cell receptor is the sodium/
major component of HBsAg particles; it self-associates into bile acid cotransporter (sodium taurocholate cotransport-
22-nm spherical particles that are released from the cells. ing polypeptide [NTCP]). On penetration into the cell, the
The filamentous particles of HBsAg found in serum contain nucleocapsid delivers the genome to the nucleus, where the
mostly S, as well as small amounts of the M and L glycopro- partial DNA strand of the genome is completed to form a
teins and other proteins and lipids. There are 10 genotypes complete double-stranded DNA circle, which is a viral mini-
and serotypes of HBV.  chromosome. Transcription of the genome is controlled by
cellular transcription elements found in hepatocytes. The
REPLICATION DNA is transcribed from different starting points on the cir-
The replication of HBV is unique for several reasons (see Box cle but have the same 3′ end. There are three major classes
55.4). First, HBV has a distinctly defined tropism for the liver. (2100, 2400, and 3500 bases) and two minor classes (900
Its small genome also necessitates economy, as illustrated by bases) of overlapping messenger RNAs (mRNAs) (Fig. 55.6).
the pattern of its transcription and translation. In addition, The 3500-base mRNA is larger than the genome. It encodes
HBV replicates through an RNA intermediate and produces and the HBc and HBe antigens, the polymerase, and a protein
releases antigenic decoy particles (HBsAg) (Fig. 55.5). primer for DNA replication and acts as the template for

Hepatitis B viral genome

Partial Virion HBsAg envelope pre-S1 pre-S2 S
double-stranded Core Large S S
DNA genome S gp39, gp42
pre-S2 HBsAg gp33, gp37
Middle S gp24, gp26

Small S

Core

3.5 kb RNprAe-S1 3172 pre-S2 1374 00 155
3155
gion P
Completion of double- 2848 G
stranded DNA genome
Gene C trantrad00nd ene S
28؉s ؊s 3182/1 3؅
00
4

Transcription

2450

2400 800 2.1 kb RNA

Nucleus Translation 2357 833
Reverse
Cytoplasm transcription DR1 12 Re
(ϩ) DNA
(Ϫ) DNA RNA pre-C 5؅ 1600
Core
5؅ DR2
Partial (Ϫ) DNA
double-stranded AAAAA~A~ 1901
DNA genome 1934 18181836

1814
1621
HBsAg Region X

* Core Core Precorep25
p23
HBeAg

p21 HBeAg p15-18
HBcAg

HBV Fig. 55.6  DNA, RNA, messenger RNA (mRNA), and proteins of hepa-
titis B virus. The inner green circles represent the DNA genome, with
Fig. 55.5  Replication of hepatitis B virus (HBV). After entry into the the nucleotide number at the center. DR1 and DR2 are direct repeat
hepatocyte and uncoating of the nucleocapsid core, the partially dou- sequences of DNA and are important for replication and integration
ble-stranded deoxyribonucleic acid (DNA) genome is delivered to the of the genome. The 3500-base transcript (outer black thin-line circle)
nucleus and completed. Transcription of the genome produces four is larger than the genome and is the template for replication of the
messenger RNAs (mRNAs), including an mRNA larger than the genome genome. Bold arcs represent mRNA for viral proteins. Note that sev-
(3500 bases). The mRNA then moves to the cytoplasm and is translated eral proteins are translated from the same mRNA but from different
into protein. Core proteins assemble around the 3500-base mRNA, and AUG codons and that different mRNAs overlap. AAA, 3′ PolyA (poly-
negative-sense DNA is synthesized by a reverse transcriptase activity in adenylate) at end of mRNA; AUG, adenine, uracil, guanine; C, C mRNA
the core. The ribonucleic acid (RNA) is then degraded while a positive- for hepatitis B core antigen (HBcAg); HBsAg, hepatitis B surface anti-
sense (+) DNA is synthesized. The filled core associates with HBsAg- gen; l, large glycoprotein; m, medium glycoprotein; P, polymerase; s,
containing endoplasmic reticulum membranes, is enveloped before small glycoprotein; S, mRNA for HBs antigen; X, X mRNA. (From Cohen,
completion of the positive-sense DNA, and is then released by exo- J., Powderly, W.G., Opal, S.M., 2010. Infectious Diseases, third ed. Mosby,
cytosis with HBsAg-containing particles. HBeAg, Hepatitis Be antigen; Philadelphia, PA.)
HBsAg, hepatitis B surface antigen.

556 SECTION 5  •  Virology

replication of the genome. The HBe and HBc are related pro- release has ended and until the infection is resolved. An indi-
teins that are translated from different in-phase start codons vidual is highly infectious when both the HBsAg and the HBeAg
of closely related mRNAs. This causes differences in their components of the virion can be detected in the blood.
processing and structure, with shedding of the HBe from the
cell and incorporation of HBc into the virion. Similarly, the Cell-mediated immunity and inflammation are respon-
2100-base mRNA encodes the small and medium glycopro- sible for causing the symptoms and effecting resolution of
teins from different in-phase start codons. The 2400-base the HBV infection by eliminating the infected hepatocyte.
mRNA, that encodes the large glycoprotein, overlaps the An insufficient T-cell response to the infection generally
2100-base mRNA. The 900-base mRNA encodes the X pro- results in the occurrence of mild symptoms, an inability to
tein, which promotes viral replication as a transactivator of resolve the infection, and the development of chronic hepa-
transcription and as a protein kinase. titis (“no pain, no gain”) (see Fig. 55.7). Chronic infection
also exhausts CD8 T cells, preventing them from killing
Replication of the genome uses the larger than genome infected cells. Antibody (as generated by vaccination) can
3500-base mRNA. This is packaged into the core nucleo- protect against initial infection by preventing delivery of the
capsid that contains the RNA-dependent DNA polymerase virus to the liver. Later in the infection, the large amount of
(P protein). This polymerase has reverse transcriptase HBsAg in serum binds to and blocks the action of neutral-
and ribonuclease H activity, but HBV lacks the integrase izing antibody, which limits the antibody’s ability to resolve
activity of the retroviruses. The 3500-base RNA acts as a an infection. Immune complexes formed between HBsAg
template, and negative-strand DNA is synthesized using and anti-HBs contribute to the development of hypersensi-
a protein primer from the P protein, which remains cova- tivity reactions (type III), leading to problems such as vas-
lently attached to the 5′ end. After this, the RNA is degraded culitis, arthralgia, rash, and renal damage.
by the ribonuclease H activity as the positive-strand DNA
is synthesized from the negative-sense DNA template. Antibodies to HBc and HBe are present in serum but
However, this process is interrupted by envelopment of cannot neutralize infection and are nonprotective. The
the nucleocapsid at the HBsAg-containing endoplasmic HBeAg protein and HBsAg are released from the cell, elicit
reticulum membrane, capturing genomes containing a and are exposed to antibody in the blood, and are bound
complete circular and incomplete DNA strand. The virion to their respective antibodies. As such, Anti-HBe and
and HBsAg-containing particles are then released from the
hepatocyte by exocytosis, without killing the cell. HBV Effective HBV
HBV cell-mediated HBV
The entire genome can also be integrated into the host HBV immune response HBV
cell chromatin. HBsAg, but not other proteins, can often
be detected in the cytoplasm of cells containing integrated Acute disease Resolution
HBV DNA. Integrated viral DNA is present in hepatocellular
carcinomas.  Symptoms:

PATHOGENESIS AND IMMUNITY Jaundice
HBV is a noncytolytic virus that causes disease by initiating
inflammation of the liver. HBV can cause acute or chronic, Release of enzymes
symptomatic or asymptomatic disease. Which of these
occurs is determined by the person’s immune response to HBV Limited HBV
the infection (Fig. 55.7). HBV cell-mediated HBV
HBV immune response HBV
The major source of infectious virus is blood, but HBV
can be found in semen, saliva, milk, vaginal and men- Chronic disease
strual secretions, and amniotic fluid. The most efficient way Mild symptoms
to acquire HBV is through injection of the virus into the
bloodstream (Fig. 55.8). Common but less efficient routes DELTA
of infection are sexual contact and birth. The virus starts AGENT
to replicate in hepatocytes of the liver within 3 days of its
acquisition, with minimal cytopathic effect. Symptoms may HBV Fulminant
not be observed for 45 days or longer, because they are pri- HBV hepatitis
marily caused by immunopathology. The infectious dose,
the route of infection, and the person’s immune response Primary
determine the incubation period. Infection proceeds for hepatocellular
a relatively long time without causing liver damage (i.e., carcinoma
elevation of liver enzyme levels) or symptoms. Copies of
the HBV genome remain in the nucleus for long periods as Cirrhosis
small circular DNA minichromosomes or can integrate into
the hepatocyte chromatin. The minichromosomes can gen- Fig. 55.7  Major determinants of acute and chronic hepatitis B virus
erate virus and HBsAg. Intracellular buildup of filamentous (HBV) infection. HBV infects the liver but does not cause direct cyto-
forms of HBsAg can produce the ground-glass hepatocyte pathology. Cell-mediated immune lysis of infected cells produces the
cytopathology characteristic of HBV infection. HBsAg par- symptoms and resolves the infection. Insufficient immunity can lead
ticles continue to be released into the blood even after virion to chronic disease. Chronic HBV disease predisposes a person to more
serious outcomes. Purple arrows indicate symptoms; green arrows indi-
cate a possible outcome.

55  •  Hepatitis Viruses 557

Anti-HBs antibodies are not detectable while the antigen symptoms. As many as 90% of infants infected perinatally
is produced. The HBc antigen is present in cells or virions become chronic carriers. Viral replication persists in these
and inaccessible to the antibody in blood. As a result, anti- people for long periods.
HBc is free to be detected throughout and after the course
of the infection. During the acute phase of infection, the liver paren-
chyma shows degenerative changes consisting of cellular
Infants and young children have an immature cell- swelling and necrosis, especially in hepatocytes surround-
mediated immune response and are less able to resolve the ing the central vein of a hepatic lobule. The inflammatory
infection, but they suffer less tissue damage and have milder cell infiltrate is mainly composed of lymphocytes. Tissue
damaging inflammation results from the combined actions
Immune complex of cytolytic cells and the inflammatory cytokines that they
diseases produce. Resolution of the infection allows the parenchyma
to regenerate. Fulminant infections, activation of chronic
Immune complexes HBsAg Symptoms, infections, or co-infection with the delta agent can lead to
Ab resolution permanent liver damage and cirrhosis. 

Liver Viremia EPIDEMIOLOGY
In the United States, more than 12 million people have
Blood IV drug CMI been infected with HBV (1 of 20), with 5000 deaths per
abuse Antibody Prevent spread year. In the world, one of three people have been infected
Sex (Ab) with HBV, with approximately 1 million deaths per year.
and disease More than 350 million people worldwide have chronic HBV
infection. In developing nations, as many as 15% of the
Blood population may be infected during birth or childhood. High
rates of seropositivity are observed in Italy, Greece, Africa,
Neonatal Mother's Vaginal Blood Semen Saliva and Southeast Asia (Fig. 55.9). In some areas of the world
Mode of infection milk secretions (southern Africa and southeastern Asia), the seroconver-
sion rate is as high as 50%. PHC, a long-term sequela of the
Transmission infection, is also endemic in these regions.

Fig. 55.8  Spread of hepatitis B virus (HBV) in the body. Initial infec- The many asymptomatic chronic carriers with virus
tion with HBV occurs through injection, unprotected sex, and birth. in blood and other body secretions foster spread of the
The virus then spreads to the liver, replicates, induces a viremia, and virus. In the United States, 0.1% to 0.5% of the general
is transmitted in various body secretions in addition to blood to start population are chronic carriers, but this is very low com-
the cycle again. Symptoms are caused by cell-mediated immunity (CMI) pared with many areas of the world. Carrier status may be
and immune complexes between antibody and hepatitis B surface lifelong.
antigen (HBsAg). IV, Intravenous.
The virus is spread by sexual, parenteral, and perinatal
routes. Transmission occurs through contaminated blood
and blood components by transfusion, needle sharing, acu-
puncture, ear piercing, or tattooing and through very close

HBsAg Prevalence
≥8%—High

2%-7%—Intermediate

<2%—Low
High incidence of
liver cancer (PHC)

Fig. 55.9  Worldwide prevalence of hepatitis B carriers and primary hepatocellular carcinoma (PHC). HBsAg, Hepatitis B surface antigen. (Courtesy Cen-
ters for Disease Control and Prevention, Atlanta, Georgia.)

558 SECTION 5  •  Virology

BOX 55.5  High-Risk Groups for Hepatitis B Acute hepatitis B
Virus Infection
90% 1%
People from endemic regions (i.e., China, parts of Africa, Alaska, Resolution 9%
Pacific Islands)
Fulminant hepatitis
Babies of mothers with chronic hepatitis B virus
Intravenous drug abusers HBsAg؉ for Ͼ6 months
People with multiple sex partners
Health care personnel who have contact with blood 50%
Residents and staff members of institutions for the mentally
Resolution Asymptomatic Chronic persistent Chronic active
retarded carrier state hepatitis hepatitis
Hemophiliacs and other patients requiring blood and blood
Extrahepatic disease: Cirrhosis Hepatic cell
product treatmentsa Polyarteritis nodosum carcinoma
Hemodialysis patients and blood and organ recipientsa Glomerulonephritis

a Screening of blood, blood products, and transplantable organs have
minimized risk.

Fever, rash, arthritis ≈15% Fig. 55.11  Clinical outcomes of acute hepatitis B infection. HBsAg,
Hepatitis B surface antigen. (Modified from White, D.O., Fenner, F., 1986.
Medical Virology, third ed. Academic, New York.)

Jaundice CLINICAL SYNDROMES

Dark urine Acute Infection
Malaise 95% As already noted, the clinical presentation of HBV in chil-
Anorexia 90% dren is less severe than that in adults, and infection may
even be asymptomatic. Clinically apparent illness occurs
Exposure Nausea 80% in as many as 25% of those infected with HBV (Figs.
55.10–55.12).
RUQ pain 60%
HBV infection is characterized by a long incubation
Itching 10% period and an insidious onset. Symptoms during the
prodromal period may include fever, malaise, and anorexia,
Incubation Preicteric Icteric Convalescent followed by nausea, vomiting, abdominal discomfort, and
period period chills. The classic icteric symptoms of liver damage (e.g.,
jaundice, dark urine, pale stools) follow soon thereafter.
Acute disease Recovery is indicated by a decline in the fever and renewed
appetite.
Fig. 55.10  Symptoms of typical acute viral hepatitis B infection are
correlated with the four clinical periods of this disease. RUQ, Right Fulminant hepatitis occurs in approximately 1% of icteric
upper quadrant. (Modified from Hoofnagle, J.H., 1983. Type A and type B patients and may be fatal. It is marked by more severe symp-
hepatitis. Laboratory Medicine 14, 705–716.) toms and indications of severe liver damage, such as ascites
and bleeding.
personal contact involving the exchange of semen, saliva,
and vaginal secretions (e.g., sex, childbirth) (see Fig. 55.8). HBV infection can promote hypersensitivity reactions
Medical personnel are at risk in accidents involving needle- that are caused by immune complexes of HBsAg and anti-
sticks or sharp instruments. People at particular risk are body. These may produce rash, polyarthritis, fever, acute
listed in Box 55.5. Sexual promiscuity and drug abuse are necrotizing vasculitis, and glomerulonephritis. 
major risk factors for HBV infection. HBV can be transmit- Chronic Infection
ted to babies through contact with the mother’s blood at Chronic hepatitis occurs in 5% to 10% of people with HBV
birth and in the mother’s milk. Babies born to chronic HBV- infections, usually after mild or inapparent initial disease.
positive mothers are at highest risk for infection. Serologic Approximately one-third of these people have chronic active
screening of donor units in blood banks has greatly reduced hepatitis, with continued destruction of the liver leading
the risk of acquisition of the virus from contaminated blood to scarring of the liver, cirrhosis, liver failure, or PHC. The
or blood products. Safer sex habits adopted to prevent human other two-thirds have chronic passive hepatitis and are less
immunodeficiency virus (HIV) transmission and the admin- likely to have problems. Chronic hepatitis may be detected
istration of the HBV vaccine have also been responsible for accidentally by finding elevated liver enzyme levels on a
decreasing the transmission and incidence of HBV. routine blood chemistry profile. Chronically infected people
are the major source for spread of the virus and are at risk
One of the major concerns related to HBV is its associa- for fulminant disease if they become co-infected with HDV. 
tion with PHC. This type of carcinoma probably accounts Primary Hepatocellular Carcinoma
for 250,000 to 1 million deaths per year worldwide; in the The World Health Organization estimates that 80% of all
United States, approximately 5000 deaths per year are cases of PHC can be attributed to chronic HBV infections.
attributed to PHC. 

55  •  Hepatitis Viruses 559

The HBV genome is integrated into these PHC cells, and the of HBV, and nearly half die of PHC or cirrhosis. PHC, like
cells express HBV antigens. PHC is usually fatal and is one cervical cancer, is a vaccine-preventable human cancer.
of the three most common causes of cancer mortality in the
world. In Taiwan, at least 15% of the population are carriers HBV may induce PHC by promoting continued liver repair
and cell growth in response to inflammation and tissue dam-
Jaundice age or by integrating into the host chromosome and stimu-
Symptoms lating cell growth directly. Such integration can stimulate
genetic rearrangements, juxtapose viral promoters next
Virus HBsAg Anti-HBs to cellular growth-controlling genes, disrupt chromosome
shedding “window” structure, and stimulate error prone DNA repair. The HBV X
Anti-HBc gene also can transactivate (turn on) the transcription of cel-
HBsAg lular proteins and stimulate cell growth and viability. These
HBeAg Anti-HBe actions can promote a subsequent mutation to promote car-
Liver enzymes cinogenesis. The latency period between HBV infection and
123 4 5 6 12 24 PHC may be as short as 9 years or as long as 35 years. 

A Months after exposure LABORATORY DIAGNOSIS
The initial diagnosis of hepatitis can be made on the basis
Symptoms Anti-HBc of the clinical symptoms and the presence of liver enzymes
in the blood (see Fig. 55.12). However, the serology of HBV
HBsAg Anti-HBe infection describes the course and nature of the disease (Table
HBeAg 55.2). Acute and chronic HBV infections can be distin-
guished by the presence of HBsAg and HBeAg in the serum
Virus Liver enzymes and the pattern of antibodies to the individual HBV antigens.
shedding
HBsAg and HBeAg are secreted into the blood during
123456 1 2 3 4 5 6 7 89 viral replication. Detection of HBeAg is the best correlate
B Months Years to the presence of infectious virus. A chronic or unresolved
Time after exposure infection can be distinguished by the continued finding of
HBeAg, HBsAg, or both, and a lack of detectable antibody
Fig. 55.12  (A) Serologic events associated with the typical course to these antigens. Antibody to HBsAg indicates resolution
of acute hepatitis B disease. (B) Development of the chronic hepatitis of infection or vaccination. Immune complexes of HBeAg
B virus carrier state. Routine serodiagnosis depends on detection of and HBsAg and antibody inhibit antibody production and
immunoglobulin M anti-HBc during the “hepatitis B surface antigen obscure detection of the complexed antigen. Although for
(HBsAg) window,” when HBs and anti-HBs are undetectable. Anti-HBc, different reasons, HBsAg/anti-HBs, HBeAg/anti-HBe, and
Antibody to hepatitis B core antigen [HBcAg]; Anti-HBe, antibody to Clark Kent/Superman can never be seen together at the
hepatitis Be antigen [HBeAg]; Anti-HBs, antibody to HBsAg. (Modified same time.
from Hoofnagle, J.H., 1981. Serologic markers of hepatitis B virus infection.
Annual Review of Medicine 32, 1–11.) Antibody to HBcAg indicates current or prior infection
by HBV, and IgM anti-HBc is the best way to diagnose a
recent acute infection, especially while the infection is
being resolved and when neither HBsAg nor anti-HBs can
be detected (the window).

The amount of virus in blood can be determined by quan-
titative genome assays using PCR and related techniques.
Knowing the viral load can help to follow the course of
chronic HBV infection and antiviral drug efficacy. 

TABLE 55.2  Interpretation of Serologic Markers of Hepatitis B Virus Infection

Serologic DISEASE STATE HEALTHY STATE
Reactivity
Early (Presymptomatic) Early Acute Acute Chronic Late Acute Resolved Vaccinated
+/−
Anti-HBc − − +a + +/− + −
Anti-HBe − − −− − +/−b −
Anti-HBs − − −− −
HBeAg − + ++ + ++
+
−−

HBsAg + + ++ −−
Infectious virus + + ++
−−

aAnti-HBc immunoglobulin M should be present.
bAnti-HBe may be negative after chronic disease.
HBc, Hepatitis B core; HBeAg, hepatitis Be antigen; HBsAg, hepatitis B surface antigen.

560 SECTION 5  •  Virology Hepatitis C and G Viruses

TREATMENT, PREVENTION, AND CONTROL HCV was identified in 1989 after isolation of a viral RNA
Hepatitis B immunoglobulin may be administered from a chimpanzee infected with blood from a person with
within a week of exposure and to newborn infants of NANBH. The viral RNA obtained from blood was con-
HBsAg-positive mothers to prevent and ameliorate disease. verted to DNA with reverse transcriptase, its proteins were
Chronic HBV infection can be treated with drugs targeted expressed, and antibodies from people with NANBH were
at the polymerase (e.g., lamivudine, entecavir, telbivu- then used to detect the viral proteins. These studies led to
dine or tenofovir, which are HIV reverse transcriptase the development of ELISA, genomic, and other tests for
inhibitors) or the nucleoside analogs adefovir dipivoxil detection of the virus.
and famciclovir. These U.S. Food and Drug Administra-
tion (FDA)-approved treatments are taken for 1 year. Unfor- HCV is the predominant cause of NANBH viral infections
tunately, antiviral drug resistance can develop. Pegylated and was the major cause of posttransfusion hepatitis before
interferon (IFN)-α also can be effective and is taken for at routine screening of the blood supply for HCV. There are
least 4 months. more than 180 million carriers of HCV in the world, which
is 3% of the population, and more than 4 million in the
Transmission of HBV in blood or blood products has been United States. HCV is transmitted by means similar to HBV
greatly reduced by screening donated blood for the pres- but has an even greater potential for establishing persistent
ence of HBsAg and anti-HBc. Additional efforts to prevent chronic hepatitis. Many HCV-infected individuals also are
transmission of HBV include safe sex and avoiding lifestyles infected with HBV or HIV. The chronic hepatitis often leads
that facilitate spread of the virus. Household contacts and to cirrhosis and potentially to hepatocellular carcinoma.
sexual partners of HBV carriers are at increased risk, as
are patients undergoing hemodialysis, recipients of pooled STRUCTURE AND REPLICATION
plasma products, health care workers exposed to blood, and HCV is the only member of the Hepacivirus genus of the Fla-
babies born to HBV-carrier mothers. viviridae family. There are seven major genotypes of HCV
(clades), up to a hundred subtypes, and extensive genetic
Vaccination is recommended for infants, children, and and antigenic diversity within each subtype. HCV is 30 to
especially for people in high-risk groups (see Box 55.5). 60 nm in diameter, has a positive-sense RNA genome,
Vaccination is useful even after exposure for newborns of and is enveloped. The genome of HCV (9100 nucleo-
HBsAg-positive mothers and people accidentally exposed tides) encodes 10 proteins, including two glycoproteins
either percutaneously or permucosally to blood or secre- (E1, E2) (Fig. 55.13). The viral RNA-dependent RNA
tions from an HBsAg-positive person. Immunization of polymerase is error prone and generates mutations in
mothers should decrease the incidence of transmission to the glycoprotein and other genes. This generates antigenic
babies and older children, which also reduces the number variability and antiviral drug resistance. Such variability
of chronic HBV carriers. Prevention of chronic HBV will makes development of a vaccine very difficult.
reduce the incidence of PHC. The single serotype and lim-
ited host range (humans) of HBV help facilitate the success HCV infects only humans and chimpanzees. HCV binds
of the immunization program. to multiple cell-surface receptors expressed on hepatocytes
and B lymphocytes that also facilitate its entry into the cell.
The HBV vaccines form virus-like particles. The ini- The receptors include CD81 (tetraspanin) surface receptors,
tial HBV vaccine was derived from the 22-nm HBsAg scavenger receptor class B type I (SRB1), and use tight junc-
particles in human plasma obtained from chronically tion proteins claudin-1 and occludin as co-receptors. HCV
infected people. The more recent vaccines are geneti- can also coat itself with low-density lipoprotein or very low
cally engineered by the insertion of a plasmid contain- density lipoprotein and then use the lipoprotein receptor to
ing the S gene for HBsAg into a yeast (Saccharomyces facilitate uptake into hepatocytes. After entry, the virus repli-
cerevisiae). The protein self-assembles into particles, cates like other flaviviruses. The virion assembles at and buds
which enhances its immunogenicity, and is adminis- into the endoplasmic reticulum and remains cell associated.
tered with alum. The vaccine must be given in a series of HCV proteins inhibit apoptosis and IFN-α action by binding
three injections, with the second and third given 1 and 6 to the tumor necrosis factor receptor and to protein kinase R
months after the first. and proteolytically degrading other proteins in the interferon
pathways. In addition to acting with the polymerase, the
A new HBV vaccine, Heplisav-B, is for adults aged 18 NS5A protein acts on interferon and other host pathways.
and older. It incorporates the yeast-derived HBsAg par- These actions prevent the death of the host cell and promote
ticles with a cytosine phosphorothioate guanosine (CpG) escape from host protections to promote persistent infection. 
oligodeoxynucleotide (CpG-ODN) adjuvant. This Toll-like
receptor 9 stimulating adjuvant improves the immunoge- PATHOGENESIS
nicity of the vaccine. Only two injections, 1 month apart, The ability of HCV to remain cell associated and prevent
are required. host cell death promotes persistent infection but results in
liver disease later in life. Up to 1012 particles per day can
Universal blood and body fluid precautions are used be produced in chronically infected, potentially asymptom-
to limit exposure to HBV. It is assumed that all patients are atic individuals. The virus’ ability to evade interferon action
infected. Gloves are required for handling blood and body and mutate to change its antigenicity helps the virus escape
fluids; wearing protective clothing and eye protection may
also be necessary. Special care should be taken with nee-
dles and sharp instruments. HBV-contaminated materials
can be disinfected with 10% bleach solutions, but unlike
most enveloped viruses, HBV is not readily inactivated by
detergents. 

55  •  Hepatitis Viruses 561

C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B
Polymerase
Glycoproteins Ion Serine protease
channel
Capsid Polymerase
Auto- component
protease
Regulator of
polymerase,
assembly, and
cell modulator

Fig. 55.13  Outcomes of hepatitis C virus infection. Enzymes in green are targets for antiviral drugs.

immune control and establish chronic disease. Cell-medi- BOX 55.6  Epidemiology of Hepatitis B, C,
ated immune responses are necessary to resolve the infec- and D Viruses
tion, but they also cause tissue damage. Antibody to HCV
is not protective. As for HBV, once established, the chronic Disease/Viral Factors
infection can exhaust CD8 cytotoxic T cells so they cannot
resolve the infection. The extent of lymphocytic infiltration, Enveloped virus is labile to drying. HBV is less sensitive to deter-
inflammation, portal and periportal fibrosis, and lobular gents than other enveloped viruses.
necrosis in liver biopsies can be used to grade the severity of
disease. It has been suggested that the cytokines of inflam- Virus is shed during asymptomatic periods.
mation and continual liver repair and induction of cell HBV (10%) and HCV (70%) cause chronic infection with potential
growth occurring during chronic HCV infection are predis-
posing factors in the development of PHC.  virus shedding. 

EPIDEMIOLOGY Transmission
HCV is transmitted primarily and efficiently in infect-
ed blood and less efficiently sexually. Intravenous drug In blood, semen, and vaginal secretions (HBV: saliva and mother’s
abusers and tattoo recipients are at the highest risk of ac- milk)
quiring HCV infection. Screening procedures have led to a
reduction in the levels of transmission by blood transfusion Via transfusion, needlestick injury, shared drug paraphernalia,
and organ donation (Box 55.6). Almost all (>90%) HIV- sexual intercourse, and breast-feeding. 
infected people who are or were intravenous drug users are
infected with HCV. Babies born of HCV-positive mothers are Who Is at Risk?
also at increased risk for infection. HCV is especially prev-
alent in southern Italy, Spain, central Europe, Japan, and Children: mild asymptomatic disease with establishment of
parts of the Middle East (e.g., almost 20% of Egyptian blood chronic infection.
donors are HCV positive). The prevalence of HCV in indi-
viduals born between 1945 and 1965 (“baby boomers”) is Adults: insidious onset of hepatitis.
approximately six times higher than the rest of the popula- HBV-infected people co-infected or superinfected with HDV:
tion. The high incidence of chronic asymptomatic in-
fections promotes the spread of the virus in the population.  abrupt, more severe symptoms with possible fulminant disease.
Adults with chronic HBV or HCV: at high risk for cirrhosis and
CLINICAL SYNDROMES
HCV causes three types of disease (Fig. 55.14): (1) acute primary hepatocellular carcinoma. 
hepatitis with resolution of the infection and recovery in
15% of cases, (2) chronic persistent infection with possible Geography/Season
progression to disease much later in life for 70% of infected
persons, and (3) severe rapid progression to cirrhosis in 15% Viruses are found worldwide.
of patients (Clinical Case 55.1). A viremia can be detected There is no seasonal incidence. 
within 1 to 3 weeks of a transfusion of HCV-contaminated
blood. The viremia lasts 4 to 6 months in people with an acute Modes of Control
infection and longer than 10 years in those with a persistent
infection. In its acute form, HCV infection is similar to acute Avoidance of high-risk behavior.
HAV and HBV infection, but the inflammatory response is HBV: virus-like particle (HBsAg) vaccines.
HBV and HCV screening of blood supply.

HBV, Hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus.

less intense and the symptoms are usually milder. More com-
monly (>70% of cases), the initial disease is asymptomatic
but establishes chronic persistent disease. The predominant
symptom is chronic fatigue. Chronic persistent disease often
progresses to chronic active hepatitis within 10 to 15 years
and to cirrhosis (20% of chronic cases) and liver failure (20%
of cirrhotic cases) after 20 years. HCV-induced liver damage
may be exacerbated by alcohol, certain medications, and
other hepatitis viruses to promote cirrhosis. HCV promotes
the development of hepatocellular carcinoma after 30 years
in up to 5% of chronically infected patients. 

562 SECTION 5  •  Virology

15% Hepatitis C virus 70% people, immunocompromised patients, or those receiving
acute infection hemodialysis. Genome detection and quantitation by RT-PCR,
branched-chain DNA, and related techniques is the gold stan-
15% dard for confirming a diagnosis of HCV and for following the
success of antiviral drug therapy. Genetic assays are less strain
Recovery and Cirrhosis Persistent specific and can detect HCV RNA in seronegative people. 
clearance rapid onset infection TREATMENT, PREVENTION, AND CONTROL
New HCV antiviral regimens using direct acting antivi-
40% rals (DAAs) has made it possible to cure 90% of individuals
infected with HCV (Table 55.3) and have replaced previous
Asymptomatic therapies. These drugs target the protease (NS3/4A), the
NS5A protein, and the polymerase (NS5B). The polymerase
? inhibitors include nucleotide analogs and nonnucleotide ana-
Chronic hepatitis logs. These antiviral drugs are usually administered as mix-
tures. Recombinant IFN-α or pegylated interferon (treated
6% 20% 4% with polyethylene glycol to enhance its biological lifetime),
alone or with ribavirin, were the only available treatments
Liver failure Cirrhosis Hepatocellular for HCV until 2011, when the first two virus-specific protease
carcinoma inhibitors were approved for use. This combination was less
effective with more side effects.
Fig. 55.14  Hepatitis C proteins and their function. Highlighted pro-
teins are targets for antiviral drugs. (Adapted from Scheel, T.K.H., Rice, Precautions for preventing the transmission of HCV are
C.M., 2013. Understanding the hepatitis C virus life cycle paves the way for similar to those for HBV and other blood-borne pathogens.
highly effective therapies. Nature Medicine 19 [7], 837–849.) The blood supply and organ donors are screened for HCV.
Persons with HCV should not share any personal care items
Clinical Case 55.1  Hepatitis C Virus or syringe needles that may get contaminated with blood
and should practice safe sex. Alcohol drinking should be lim-
In a case reported by Morsica and associates (Scand J Infect ited because it exacerbates the liver damage caused by HCV. 
Dis 33:116–120, 2001), a 35-year-old woman was admit-
ted with malaise and jaundice. Elevated blood levels of Hepatitis G Virus
bilirubin (71.8 μmol/L; normal value < 17 μmol/L) and ALT
(410 IU/l; normal value < 30 IU/L) indicated liver damage. HGV (also known as GB virus-C [GBV-C]) resembles HCV in
Serology was negative for antibodies to hepatitis A, hepatitis many ways. HGV is a flavivirus, is transmitted in blood, and
B, hepatitis C, Epstein-Barr virus, cytomegalovirus, and HIV- has a predilection for chronic hepatitis infection. It is identi-
1. However, HCV genomic RNA sequences were detected by fied by detection of the genome by RT-PCR or other RNA
reverse transcriptase polymerase chain reaction analysis. detection methods. 
ALT levels peaked on the third week after admission and
returned to normal by the eighth week. HCV genomes in Hepatitis D Virus
blood were undetectable by the eighth week. Anti-HCV anti-
body was also detected by the eighth week. It was suspected Approximately 15 million people in the world are infected
that she was infected by her sexual partner, and this was with HDV (delta agent), and the virus is responsible for caus-
confirmed by genotyping virus obtained from both individu- ing 40% of fulminant hepatitis infections. HDV is unique
als. Confirmation was provided by partial sequence analysis in that it uses HBV and target cell proteins to replicate and
of the E2 gene from the two viral isolates. The 5% genetic produce its one protein. It is a viral parasite, proving that
divergence detected between the isolates was less than the “even fleas have fleas.” HBsAg is essential for packag-
≈20% divergence expected for unrelated strains. Before the ing the virus. The delta agent resembles plant virus sat-
analysis, the sexual partner was unaware of his chronic ellite agents and viroids in its size, genomic structure, and
HCV infection. Even more than HBV, which is also transmit- requirement for a helper virus for replication (Fig. 55.15).
ted by sexual and parenteral means, HCV causes inapparent
and chronic infections. Inapparent transmission of the virus, STRUCTURE AND REPLICATION
as in this case, enhances spread of the virus. The molecular The HDV RNA genome is very small (≈1700 nucleo-
analysis demonstrates the genetic instability of the HCV tides), and unlike other viruses, the single-stranded RNA is
genome, which is a possible mechanism for facilitating its circular and forms a rod shape as a result of its extensive
chronic infection by changing its antigenic appearance to base pairing. The virion is approximately the same size as
promote escape from the immune response. the HBV virion (35 to 37 nm in diameter). The genome is
surrounded by the delta antigen core, which, in turn, is
ALT, Aspartate amino transferase; HBV, hepatitis B virus; HCV, surrounded by an HBsAg-containing envelope. The delta
hepatitis C virus. antigen exists as a small (24-kDa) or large (27-kDa) form;
the small form is predominant.
LABORATORY DIAGNOSIS
The diagnosis and detection of HCV infection are based on
ELISA recognition of anti-HCV antibody or detection of the
RNA genome. Seroconversion occurs within 7 to 31 weeks of
infection. ELISA is used for screening the blood supply from
normal donors. Antibody is not always detectable in viremic

55  •  Hepatitis Viruses 563

TABLE 55.3  Hepatitis C Antiviral Drugs and Combinations

Antiviral Drug Target Name
Daklinza
Daclatasvir NS5A Olysio
Simeprevir NS3/4A protease Sovaldi
Zepatier
Sofosbuvir NS5B polymerase Mavyret
Harvoni
Elbasvir-grazoprevir NS5A + NS3/4A protease Vosevi
Technivie
Glecaprevir-pibrentasvir NS3/4A protease + NS5A Viekira Pak

Ledipasvir-Sofosbuvir NS5A + NS5B polymerase Epclusa
Copegus, Rebetol, Ribosphere
Sofosbuvir-velpatasvir-voxilaprevir NS5B polymerase + NS5A + NS3/4A protease Pegasys
PegIntron
Ombitasvir-paritaprevir-ritonavir NS5A + NS3/4A protease + inhibitor of CYP3A4

Ombitasvir-paritaprevir-ritonavir- NS5A + NS3/4A protease + inhibitor of CYP3A4 +
dasabuvir NS5B polymerase

Sofosbuvir-velpatasvir NS5B polymerase + NS5A

Ribavarin Broad -spectrum antiviral

Peginterferon alfa-2a, peginterferon Pegylated natural antiviral
alfa-2b

CO-INFECTION: HBV ؉ ␦ Incubation Cirrhosis

Circular HBsAg Acute hepatitis FULMINANT
ssRNA coat HEPATITIS
Delta
antigen Incubation
SUPERINFECTION: Chronic HBV ؉ ␦
Chronic
delta infection

Fig. 55.16  Consequences of delta virus infection. Delta virus (δ)
requires the presence of hepatitis B virus (HBV) infection. Superinfec-
tion of a person already infected with HBV (carrier) causes more rapid,
severe progression than co-infection (shorter arrow).

35-40 nm with HBV and the delta agent. A person with chronic HBV
can also be superinfected with the delta agent. More rapid,
Fig. 55.15  Delta hepatitis virion. HBsAg, Hepatitis B surface antigen; severe progression occurs in HBV carriers superinfected
ssRNA, single-stranded RNA. with HDV than in people co-infected with HBV and the delta
agent because, during co-infection, HBV must first establish
The delta agent binds to and is internalized by hepatocytes its infection before HDV can replicate (Fig. 55.16), whereas
in the same manner as HBV because it has HBsAg in its enve- superinfection of an HBV-infected person allows the delta
lope. The transcription and replication processes of the HDV agent to replicate immediately and in more cells.
genome are unusual. The host cell’s RNA polymerase II makes
an RNA copy to replicate the genome. The genome then forms Unlike HBV disease, damage to the liver occurs as a result
an RNA structure called a ribozyme, which cleaves the RNA of the direct cytopathic effect of the delta agent combined
circle to produce an mRNA for the small delta antigen. The with the underlying immunopathology of the HBV disease.
gene for the delta antigen is mutated by a cellular enzyme The delta agent exacerbates the HBV disease. Persistent
(double-stranded RNA-activated adenosine deaminase) dur- delta agent infection is often established in HBV carriers.
ing infection, allowing production of the large delta antigen. Antibodies are elicited against the delta agent, but protec-
Production of this antigen limits replication of the virus but tion is provided by antibodies to HBsAg, generated by vac-
also promotes association of the genome with HBsAg to form a cination or infection, because it is the external antigen and
virion, and the virus is then released from the cell.  viral attachment protein for HDV. 

PATHOGENESIS EPIDEMIOLOGY
The delta agent can replicate and cause disease only in peo- The delta agent infects children and adults with under-
ple with active HBV infections. Because the two agents are lying HBV infection (see Box 55.6), and people who are
transmitted by the same routes, a person can be co-infected persistently infected with both HBV and HDV are a source
for the virus. The agent has a worldwide distribution,
infecting approximately 5% of the more than three hun-
dred million HBV carriers, and is endemic in southern
Italy, the Amazon Basin, parts of Africa, and the Middle
East. Epidemics of HDV infection occur in North America

564 SECTION 5  •  Virology

BOX 55.7  Clinical Summaries family with a positive-strand RNA genome and naked capsid
structure. Although HEV is found throughout the world, it is
Hepatitis A: A 37-year-old man develops fever, chills, headache, most problematic in developing countries. In developed coun-
and fatigue 4 weeks after eating at a greasy-spoon diner. tries, HEV is a zoonosis and is acquired from pigs and under-
Within 2 days, he develops anorexia, vomiting, and right upper cooked pork or game meat. Epidemics have been reported in
quadrant abdominal pain followed by jaundice, dark-colored India, Pakistan, Nepal, Burma, North Africa, and Mexico.
urine, and pale stools persisting for 12 days. Then symptoms
decrease. The symptoms and course of HEV disease are similar to
those of HAV disease; it causes only acute disease. However,
Hepatitis B: A 27-year-old IV drug user develops symptoms of the symptoms for HEV may occur later than those of HAV
hepatitis 60 days after using a dirty needle. disease. The mortality rate associated with HEV disease is
1% to 2%, approximately 10 times that associated with
Hepatitis B and D: A different IV drug user develops symptoms of HAV disease. HEV infection is especially serious in pregnant
hepatitis, altered mental capacity, and massive hepatic necrosis women (mortality rate of ≈20%).
and then dies.
  For a case study and questions see StudentConsult.com.
Hepatitis C: Elevated liver enzymes were detected in an indi-
vidual during a physical examination. Hepatitis C virus in the Bibliography
blood was detected by enzyme-linked immunosorbent assay.
Ten years later, cirrhosis and liver failure developed, requiring a Bartenschlager, R., 2013. Hepatitis C Virus: From Molecular Virology to
liver transplant. Antiviral Therapy. Current Topics in Microbiology and Immunology,
vol. 369. Springer-Verlag, Heidelberg, Germany.
IV, Intravenous.
Casey, J.L., 2006. Hepatitis Delta Virus. Current Topics in Microbiology
and Western Europe, usually in illicit drug users. HDV is and Immunology, vol. 307. Springer-Verlag, Heidelberg, Germany.
spread by the same routes as HBV, and the same groups
are at risk for infection, with parenteral drug abusers, Catalina, G., Navarro, V., Hepatitis, C., 2000. A challenge for the general-
hemophiliacs, and others receiving blood products at ist. Hosp. Pract. 35, 97–108.
highest risk. Screening of the blood supply has reduced
the risk for recipients of blood products.  Cohen, J., Powderly, W.G., 2004. Infectious Diseases, second ed. Mosby,
St Louis.
CLINICAL SYNDROMES
The delta agent increases the severity of HBV infections Dustin, L.B., Bartolini, B., Capobianchi, M.R., Pistello, M., 2016. Hepatitis
(Box 55.7). Fulminant hepatitis is more likely to develop in C virus: life cycle in cells, infection and host response, and analysis of
people infected with the delta agent than in those infected molecular markers influencing the outcome of infection and response to
with the other hepatitis viruses. This very severe form of therapy. Clin. Microbiol. Infect. 22, 826–832.
hepatitis causes altered brain function (hepatic encepha-
lopathy), extensive jaundice, and massive hepatic necrosis, Flint, S.J., Racaniello, V.R., et al., 2015. Principles of Virology, fourth ed.
which is fatal in 80% of cases. Chronic infection with the American Society for Microbiology Press, Washington, DC.
delta agent can occur in people with chronic HBV. 
Ganem, D., Prince, A.M., 2004. Hepatitis B virus infection—natural his-
LABORATORY DIAGNOSIS tory and clinical consequences. N. Engl. J. Med. 350, 1118–1119.
The presence of the agent can be noted by detecting the
RNA genome, the delta antigen, or anti-HDV antibodies. Grimm, D., Thimme, R., Blum, H.E., 2011. HBV life cycle and novel drug
ELISA and radioimmunoassay procedures are available for targets. Hepatol. Int. 5, 644–653.
detection. The delta antigen can be detected in the blood
during the acute phase of disease in a detergent-treated Hagedorn, C.H., Rice, C.M., 2000. The Hepatitis C Viruses. Current Top-
serum sample. RT-PCR techniques can be used to detect the ics in Microbiology and Immunology, vol. 242. Springer-Verlag, Berlin.
virion genome in blood. 
Knipe, D.M., Howley, P.M., 2013. Fields Virology, sixth ed. Lippincott Wil-
TREATMENT, PREVENTION, AND CONTROL liams & Wilkins, Philadelphia.
There is no known specific treatment for HDV hepatitis.
Because the delta agent depends on HBV for replication and Lok, A.S.F., 2002. Chronic hepatitis B. N. Engl. J. Med. 346, 1682–1683.
is spread by the same routes, prevention of HBV infection Tam, A.W., Smith, M.M., Guerra, M.E., et  al., 1991. Hepatitis E virus:
prevents HDV infection. Immunization with HBV vaccine
protects against delta virus infection. If a person has already molecular cloning and sequencing of the full-length viral genome. Virol-
acquired HBV, delta agent infection may be prevented by ogy 185, 120–131.
reducing risk of exposure by illicit intravenous drug use.  Tan, S.L., 2006. Hepatitis C viruses. Genomes and Molecular Biology.
Horizon. https://www.ncbi.nlm.nih.gov/books/NBK1613/.
Hepatitis E Virus Taylor, J.M., 2006. Hepatitis delta virus. Virology 344, 71–76.
Websites
HEV (E-NANBH) (the E stands for enteric or epidemic) is predom- Centers for Disease Control and Prevention, Viral hepatitis. www.cdc.gov/
inantly spread by the fecal-oral route, especially in contami- hepatitis/. Accessed September 21, 2018.
nated water (see Box 55.3). HEV is a member of the Hepeviridae Gilroy, R.K., Hepatitis, A., http://emedicine.medscape.com/arti
cle/177484-overview. Accessed September 21, 2018.
Hepatitis, B Foundation, Statistics. www.hepb.org/hepb/statistics.htm.
Accessed September 21, 2018.
Hepatitis C therapies. https://www.hepatitisc.uw.edu/page/treatment/dr
ugs. Accessed September 21, 2018.
Infectious Disease Society of America, HCV guidelines. https://www.
hcvguidelines.org/. Accessed September 21, 2018.
Mukhrjee, S., Dhawan, V.K., Hepatitis, C. http://emedicine.medscape.com
/article/177792-overview. Accessed September 21, 2018.
National Institute of Allergy and Infectious Diseases, Viral hepatitis. https://
www.niaid.nih.gov/diseases-conditions/hepatitis. Accessed September
21, 2018.
Nature: Hepatitis C. www.nature.com/nature/outlook/hepatitis-
c/index.html. Accessed September 21, 2018.
Pascarella, S., Negroa, F., Hepatitis D virus: an update. http://onlinelibra
ry.wiley.com/doi/10.1111/j.1478-3231.2010.02320.x/pdf. Accessed
September 21, 2018.
WHO Alert: Hepatitis. www.who.int/csr/disease/hepatitis/whocdscsredc2
007/en/index4.html. Accessed September 21, 2018
WHO Alert, Hepatitis C factsheet. www.who.int/mediacentre/factsheets/f
s164/en/. Accessed September 21, 2018.

Case Studies and Questions 2. What laboratory tests would have been helpful in distin-
guishing the different hepatitis infections?
A 55-year-old man (patient A) was admitted to the hospi-
tal with fatigue, nausea, and abdominal discomfort. He had 3 . What was the most likely means of viral acquisition in
a slight fever, his urine was dark yellow, and his abdomen each case?
was distended and tender. He had returned from a trip to
Thailand within the previous month. 4. What personal and public health precautions should
A 28-year-old woman (patient B) was admitted to the have been taken to prevent the transmission of virus in
hospital complaining of vomiting, abdominal discom- each case?
fort, nausea, anorexia, dark urine, and jaundice. She
admitted that she was a former heroin addict and that 5. Which of the patients was susceptible to chronic disease?
she had shared needles. In addition, she was 3 months 6. What laboratory tests distinguish acute from chronic
pregnant.
A 65-year-old man (patient C) was admitted with jaun- HBV disease?
dice, nausea, and vomiting. He had major surgery requir- 7. How can HBV disease be prevented? How could it be
ing blood transfusions when he was a child.
1 . What clinical or epidemiologic clues would have assisted treated?

in the diagnosis of hepatitis A, B, and C?

564.e1

56 Prion Diseases

A 73-year-old man complained of weakness, forget- At autopsy, brain sections showed vacuolation and
fulness, difficulty speaking, and involuntary move- amyloid-containing plaques and fibrils, but there
ments of his right arm. After 3 months, myoclonus was no evidence of inflammatory cells.
(muscle twitching) and other neurologic signs were 1. Which disease signs indicate a prion disease?
noted and he was hospitalized. Protein 14-3-3 was 2. Why are prions so resistant to disinfection?
detected in cerebrospinal fluid (CSF), but there was 3 . Why was there no evidence of an immune response?
no evidence of an infection. The patient’s condition
continued to deteriorate, he slipped into a coma,   Answers to these questions are available on
and he died 4 months after the onset of symptoms. StudentConsult.com.

Summaries Clinically Significant Organisms

PRIONS ᑏᑏ Normal PrP protein binds to the PrPSc Epidemiology
or the multimeric PrPSc, which alters its ᑏᑏ Transmitted on contaminated surgical
Trigger Words conformation and binds and extends
fibrils devices, by injection, in food, or genetic
Creutzfeldt-Jakob disease, spongiform Diagnosis
encephalopathy, kuru, presenile demen- ᑏᑏ Collect in brain, where they cause spon- ᑏᑏ Symptomatology, MRI, indirect assays
tia, myoclonus giform vacuoles Treatment, Prevention, and Control
ᑏᑏ Rigorous disinfection procedures
Biology, Virulence, and Disease ᑏᑏ No immune response, no inflammation ᑏᑏ No means of prevention or control
ᑏᑏ Acquired, genetic, and sporadic forms of
ᑏᑏ Prions are infectious protein aggregates
resistant to inactivation prion disease
ᑏᑏ Creutzfeldt-Jakob disease (presenile
ᑏᑏ Prions consist of assembled subunits
with an alternate conformation of nor- dementia), kuru, Gerstmann-Sträussler-
mal host proteins (PrP) Scheinker disease, fatal familial insomnia

MRI, Magnetic resonance imaging.

Spongiform encephalopathies, which are slow neurode- to purify, characterize, and then clone the genes for the
generative diseases, are caused by proteinaceous infectious scrapie and other prion agents and show that the disease-
particles termed prions. Unlike conventional viruses, prions related prion protein is sufficient to cause disease.
have no virion structure or genome, elicit no immune
response, and are extremely resistant to inactivation by Structure and Physiology
heat, disinfectants, and radiation (Table 56.1). Prion
diseases can be sporadic, genetic, or acquired. After The prion is an infectious protein called scrapie-like prion
long incubation periods, these agents cause damage to protein (PrPSc), which is protease resistant, hydrophobic,
the central nervous system, leading to a subacute spongi- forms fibrillar aggregates, and lacks nucleic acids. It con-
form encephalopathy. The long incubation period, which sists of an alternate conformation of a normal cell surface
can last 30 years in humans, has made the study of these glycoprotein termed cellular prion protein (PrPC) (27,000
agents difficult. to 30,000 Da). PrPC is protease sensitive and is held in the
cell membrane by a linkage between its terminal serine and
Acquired (by infection) human prion diseases include a special lipid called glycophosphatidylinositol (GPI-linked
kuru, Creutzfeldt-Jakob disease (CJD), and variant CJD protein). PrPC interacts with and modulates the function
(vCJD). Genetic prion diseases include CJD, Gerstmann- of numerous membrane proteins in the brain, including
Sträussler-Scheinker (GSS) syndrome, and fatal familial potassium channels, N-methyl-d-aspartate (NMDA) recep-
insomnia (FFI). Sporadic occurrences of CJD and FFI occur tors, and the neural cell adhesion molecule. Binding to
more commonly (85% to 90% of cases) than genetic (10% PrPSc changes the conformation of the PrPC protein, which
to 15%) or acquired (1% to 3%). The animal diseases include is rich in α-helical configuration to a β-sheet enriched form
scrapie, bovine spongiform encephalopathy (BSE; [“mad to produce the aberrant protein termed PrPSc, which builds
cow disease”]), chronic wasting disease (in mule, deer, and a fibril (Table 56.2). PrPSc is protease resistant, aggregates
elk), and transmissible mink encephalopathy (Box 56.1). into amyloid rods (fibrils), and is cell free.

Carlton Gajdusek won the Nobel Prize in 1976 for show- The current theory to explain how an aberrant pro-
ing that kuru has an infectious etiology and for developing tein could cause disease is called template-mediated protein
a method for analyzing the agent. Stanley Prusiner won refolding. A linear aggregate of PrPSc binds to an anionic
the Nobel Prize in 1997 for developing a hamster infection
model for the scrapie agent. He and his coworkers were able 565

566 SECTION 5  •  Virology

TABLE 56.1  Comparison of Classic Viruses and Prions TABLE 56.2  Comparison of Scrapie Prion Protein and
(Normal) Cellular Prion Protein
Characteristic Virus Prion

Filterable infectious agents Yes Yes Characteristic PrPSc PrPC
Presence of nucleic acid Yes No
Structure Multimeric Monomeric
Defined morphology Yes No Protease resistance Yes No
(electron microscopy)
Presence in scrapie Yes No
fibrils
Presence of protein Yes Yes

DISINFECTION BY: Location in or on cells Cytoplasmic vesicles Plasma membrane
and extracellular
Formaldehyde Yes No milieu

Proteases Some No Turnover Days Hours

Heat (80° C) Most No PrPC, Cellular prion protein; PrPSC, scrapie prion protein.

Ionizing and ultraviolet radiation Yes No
No
DISEASE Yes Specific mutations at codon 129 determine the severity
Cytopathologic effect of CJD. Conformational rather than genetic mutation is
another property that distinguishes prions from viruses.
Incubation period Depends on virus Long The different conformational strains can have different
properties and varying disease aspects (e.g., incubation
Immune response Yes No period).

Interferon production Yes No Aggregation of other proteins into prions or prion-like
structures may cause or contribute to human diseases such
Inflammatory response Yes No as Alzheimer disease, Huntington disease, and Parkinson
disease. 
BOX 56.1  Prion Diseases
Pathogenesis
Human
Kuru Prion infection can occur by ingestion, penetration through
Creutzfeldt-Jakob disease cuts in the skin, or by direct infection of the brain or neuro-
Variant CJD nal tissue with prion-containing tissue. After ingestion, the
Gerstmann-Sträussler-Scheinker syndrome prions accumulate in highly enervated secondary lymphoid
Fatal familial insomnia tissue in follicular dendritic cells and B cells and then travel
Sporadic fatal insomnia  up neurons to the central nervous system and the brain.
Animal
Scrapie (sheep and goats) Spongiform encephalopathy describes the appearance
Transmissible mink encephalopathy of the vacuolated neurons, as well as their loss of function
Bovine spongiform encephalopathy (BSE [mad cow disease]) and lack of an immune response or inflammation (Box 56.2).
Chronic wasting disease (mule, deer, and elk) The formation of amyloid-containing plaques and fibrils, a
proliferation and hypertrophy of astrocytes, and vacuola-
structure on the cell surface, such as a glycosaminoglycan, tion of neurons and adjacent glial cells are observed (Fig.
and the normal PrPC on the cell surface. This causes the 56.1). The PrPSc reaches high concentrations in the brain
PrPC to refold, acquire the structure of PrPSc, and join the and is taken up by neurons and phagocytic cells but is diffi-
chain. Binding to the PrPSc forces the α-helical structure of cult to degrade, which is a feature that may contribute to the
the PrPC to change to a more β-pleated sheet structure of the vacuolation of brain tissue. Prions can also be isolated from
PrPSc. The PrPSc acts as a template to transmit its conforma- tissue other than the brain, but only the brain shows any
tion onto each new PrPSc, which can then perpetuate the pathologic changes. No inflammation or immune response
change, analogous to how a mutation in the genetic tem- to the agent is generated, distinguishing this disease from
plate of a virus perpetuates a change in the deoxyribonucleic classic viral encephalitis. Protein markers (tau protein or
acid (DNA) or ribonucleic acid (RNA) genome. When the 14-3-3 brain protein) can be detected in the CSF of symp-
string of PrPSc breaks, it creates new primers on which more tomatic persons, but this is not specific for prion disease.
prions can be built. The PrPC continue to be made by the
cell, and as they bind to the PrPSc primers, the cycle contin- The incubation period for CJD and kuru may be as long
ues. The human version of the PrPC is encoded on chromo- as 30 years, but once the symptoms become evident, dis-
some 20. The fact that these plaques consist of host protein ease progresses rapidly and death usually occurs within
may explain the lack of an immune response to these agents a year. 
in patients with the spongiform encephalopathies.
Epidemiology
Different strains of PrPSc occur because of mutations in
the PrPC (genetic) or because of self-perpetuating alterna- CJD is transmitted predominantly by (1) injection, (2) trans-
tive folding patterns of the protein (sporadic or acquired). plantation of contaminated tissue (e.g., corneas), (3) contact

56  •  Prion Diseases 567

BOX 56.2  Pathogenic Characteristics of BOX 56.3  Epidemiology of Disease Caused
Prions by Prions

No cytopathologic effect in vitro Disease/Viral Factors
Long doubling time of at least 5.2 days
Long incubation period Agents are impervious to standard microbial disinfection proce-
Cause vacuolation of neurons (spongiform), amyloid-like plaques, dures.

gliosis Diseases have very long incubation periods, as long as 30 years.
Cause loss of muscle control, shivering, tremors, dementia Disease acquisition may be infectious, genetic, or sporadic (ran-
Lack of antigenicity
Lack of inflammation dom occurrence). 
Lack of immune response
Lack of interferon production Transmission

Phosphatidylinositol glycan Transmission is via infected tissue, or syndrome may be inher-
membrane anchored PrPc ited.

1 PrPSc aggregate Infection can occur by ingestion,through cuts in skin, transplanta-
tion of contaminated tissues (e.g., cornea), and use of contami-
2 nated medical devices (e.g., brain electrodes). 

3 Who Is at Risk?

4 Members (especially women and children) of the Fore tribe in
New Guinea were at risk for kuru because of ritual cannibalism.
5
Fig. 56.1  Template-mediated protein refolding model for prolifera- Surgeons, transplant and brain-surgery patients, and others are at
tion of prions. PrPC is a normal cellular protein that is anchored in the risk for CJD and GSS syndrome. 
cell membrane by phosphatidylinositol glycan. PrPSc is a hydrophobic
globular protein that aggregates with itself and with PrPC on the cell Geography/Season
surface (1). PrPC acquires the conformation of PrPSc (2). The cell synthe-
sizes new PrPC (3), and a chain is built along cell surface anionic gly- GSS syndrome and CJD have sporadic occurrence worldwide.
cosaminoglycans (4). The chain breaks on phagocytosis or from shear There is no seasonal incidence. 
forces and releases PrPSc aggregates that act like seed crystals to start
the cycle over. A form of PrPSc is internalized by neuronal cells and Modes of Control
accumulates (5). Other models have been proposed.
No treatments are available.
Cessation of ritual cannibalism has led to the disappearance of

kuru.
Elimination of animal products from livestock feed to prevent

vCJD development and transmission
For GSS syndrome and CJD, neurosurgical tools and electrodes

should be disinfected in 5% hypochlorite solution or 1.0 M
sodium hydroxide or autoclaved at 15 psi for 1 hour.

CJD, Creutzfeldt-Jakob disease; GSS, Gerstmann-Sträussler-Scheinker;
vCJD, variant Creutzfeldt-Jakob disease.

with contaminated medical devices (e.g., brain electrodes),
and (4) food (Box 56.3). CJD usually affects persons older
than 50 years. CJD, FFI, and GSS syndrome are also inherit-
able, and families with genetic histories of these diseases have
been identified. The diseases are rare but occur worldwide.

Kuru was limited to a very small area of the New Guinea
highlands. The name of the disease means “shivering” or
“trembling,” and the disease was related to the cannibalistic
practices of the Fore tribe of New Guinea. Before Gajdusek
intervened, it was the custom of these people to eat the bodies
of their deceased kinsmen. When Gajdusek began his study,
he noted that women and children, in particular, were the
most susceptible to the disease, and he deduced that the rea-
sons were that the women and children prepared the food,
and they were given the less desirable viscera and brains to
eat. Their risk for infection was higher because they handled
the contaminated tissue, making it possible for the agent to
be introduced through the conjunctiva or cuts in the skin. In
addition, they ingested the neural tissue, which contains the
highest concentrations of the kuru agent. Cessation of this
cannibalistic custom has stopped the spread of kuru.

An epidemic of BSE (mad cow disease) in 1980 in the
United Kingdom and the unusual incidence of a more rap-
idly progressing CJD in younger people (<45 years) in 1996
prompted concern that contaminated beef was the source

568 SECTION 5  •  Virology

of this new variant of CJD (termed vCJD). Infection of cattle encephalopathies are characterized by a loss of muscle con-
was most likely caused by the use of contaminated animal trol, shivering, myoclonic jerks and tremors, loss of coordi-
by-products (e.g., sheep entrails, brains) as a protein sup- nation, rapidly progressive dementia, and death. 
plement in cattle feed. Ingestion of contaminated beef is
likely to be the cause of 153 cases of vCJD, more than 98% Laboratory Diagnosis
of which have occurred in the United Kingdom. 
There are no methods for directly detecting prions in tis-
Clinical Syndromes sue, and there is no serologic response. The initial diagnosis
must be made on clinical grounds. Initial confirmation of
The prion agents cause a progressive, degenerative neu- the diagnosis can be made by magnetic resonance imag-
rologic disease with a long incubation period, but with ing, detection of elevated levels of 14-3-3 protein or tau
rapid progression to death after the onset of symptoms protein in CSF, or a proteinase K–resistant form of PrP in
(Fig. 56.2; Clinical Case 56.1; Box 56.4). The spongiform a Western blot using antibody to PrP in a tonsil biopsy.
The ability of PrPSc to initiate the polymerization of nor-
Infection Incubation period Prodrome Dementia/ mal PrP is utilized in the protein-misfolding cyclic assay
1-30 years myoclonic stage (PMCA) to amplify the number of PrPSc units and can be
Death used to detect the presence of prions. A new assay called
real-time quaking-induced conversion (RT-QuIC) tests
3.5 months 4 months CSF or nasal-brushing specimens for the presence of PrPSc.
The aggregation of PrP into prion fibrils enhances the fluo-
Fig. 56.2  Progression of transmissible Creutzfeldt-Jakob disease. rescence of thioflavin T, which can be readily measured.
At autopsy, the characteristic amyloid plaques, spongiform
Clinical Case 56.1 Transmission vacuoles, and immunohistologically detected PrP can be
of Creutzfeldt-Jakob Disease by observed. 
Transfusion
Treatment, Prevention, and
In a case reported by Wroe and associates (Lancet Control
368:2061–2067, 2006), a 30-year-old man consulted his
family doctor because of fatigue and inability to concen- No treatment exists for kuru or CJD. The causative agents
trate. The symptoms were attributed to a respiratory tract are also impervious to the disinfection procedures used for
infection. Neurologic exams for the patient at this time other viruses, including formaldehyde, detergents, and ion-
were normal. History was significant for the fact that dur- izing radiation. Autoclaving at 15 psi for 1 hour (instead of
ing surgery 7 years earlier, the patient had received packed 20 minutes) or treatment with 5% hypochlorite solution or
red cells, including blood from a donor who died 1 year 1.0 M sodium hydroxide can be used for decontamination.
later with vCJD. Within 6 months of his initial presenta- Because these agents can be transmitted on instruments
tion, the patient had difficulty maintaining balance, a and brain electrodes, such items should be carefully disin-
tendency to stagger, some memory problems, a tremor in fected before being reused.
his hands, and “searing pain” in his legs. At this time, there
was no evidence of changes in vision or mental status. The outbreak of BSE and vCJD in the United Kingdom
After another 6 weeks, his mental status and memory de- promoted legislation to ban animal products in livestock
creased, balance and walking became difficult and painful, feed and encouraged more careful monitoring of cattle.
magnetic resonance neuroimaging and electroencephalo- Prion disease has not been a problem in cattle in the United
gram indicated changes, and a new blood test showed the States. Cattle must be younger than 5 years old to minimize
presence of the vCJD prion protein (PrPSc). The patient’s the possibility of accumulation of aberrant PrP and so that
mental status and physical ability continued to decline; muscle tissue would have the lowest amount of PrP.
he became mute, bedridden, poorly responsive, and he
died 8 years and 8 months after the transfusion. Western BOX 56.4  Clinical Summaries
immunoblot of autopsy samples from the brain and tonsils
contained the PrPSc protein. PrP plaques and spongiform Creutzfeldt-Jakob disease: A 63-year-old man complained of
encephalopathy were noted in the brain. poor memory and difficulty with vision and muscle coordina-
tion. Over the course of the next year, he developed senile
Because of the long incubation period for prion diseases, dementia and irregular jerking movements, progressively lost
prevention of transfusion transmission of CJD is difficult. muscle function, and then died.
vCJD has a more rapid onset of disease, and this case shows
the classic progression through the five stages: (1) incuba- Variant Creutzfeldt-Jakob disease: A 25-year-old is seen by a
tion (6 years), (2) prodromal fatigue and difficulty concen- psychiatrist for anxiety and depression. After 2 months, he has
trating (18 months), (3) progressive neurologic decline problems with balance and muscle control and has difficulty
(9 months), (4) late neurologic phase (4 months), and (5) remembering. He develops myoclonus and dies within 12
terminal phase. Immunoblot analysis of treated prion pro- months of onset.
tein can now distinguish the PrPSc from the normal protein
in samples that can be taken from the patient’s tonsils (or   For a case study and questions see StudentC­ onsult.com
at autopsy, from the brain).
CJD, Creutzfeldt-Jakob disease; vCJD, variant Creutzfeldt-Jakob

disease.

56  •  Prion Diseases 569

Bibliography Orrú, C.D., Groveman, B.R., Hughson, A.G., et al., 2015. Rapid and sen-
sitive RT-QuIC detection of human Creutzfeldt-Jakob disease using
Aguzzi, A., Nuvolone, M., Zhu, C., 2013. The immunobiology of prion dis- cerebrospinal fluid. MBio.. 6 (1), e0245114. https://doi.org/10.1128/
eases. Nat. Rev. Immunol. 13, 888–902. mBio.02451-14.

Aguzzi, A., Zhu, C., 2012. Five questions on prion diseases. PLoS Pathog. Prusiner, S.B., 1992. Molecular biology and genetics of neurodegenerative
8, e1002651. diseases caused by prions. Adv. Virus. Res. 41, 241–280.

Belay, E.D., 1999. Transmissible spongiform encephalopathies in humans. Prusiner, S.B., 1996. Prions, Prions, Prions. Current Topics in Microbiol-
Annu. Rev. Microbiol. 53, 283–314. ogy and Immunology, vol. 207. Springer-Verlag, Berlin.

Brown, P., Coker-Vann, M., Pomeroy, K., et  al., 1986. Diagnosis of Prusiner, S.B., 2012. A unifying role for prions in neurodegenerative dis-
Creutzfeldt-Jakob disease by Western blot identification. N. Engl. J. Med. eases. Science 336, 1511–1512.
314, 547–551.
Richman, D.D., Whitley, R.J., Hayden, F.G., 2017. Clinical Virology,
Cohen, J., Powderly, W.G., 2004. Infectious Diseases, second ed. Mosby, fourth ed. American Society for Microbiology Press, Washington, DC.
St Louis.
Takada, L.T., Geschwind, M.D., 2013. Prion diseases. Semin. Neurol. 33,
Flint, S.J., Racaniello, V.R., et al., 2015. Principles of Virology, fourth ed. 348–356.
American Society for Microbiology Press, Washington, DC.
Websites
Halfmann, R., Alberti, S., Lindquist, S., 2010. Prions, protein homeostasis, Centers for Disease Control and Prevention, Prion diseases. https://www.
and phenotypic diversity. Trends. Cell. Biol. 20, 125–133.
cdc.gov/prions/index.html. Accessed September 22, 2018.
Hsich, G., Kenney, K., Gibbs, C.J., et al., 1996. The 14-3-3 brain protein in CJD Foundation, https://cjdfoundation.org/info.html.
cerebrospinal fluid as a marker for transmissible spongiform encepha- Freudenrich, C.C., How mad cow disease works. https://animals.howstu
lopathies. N. Engl. J. Med. 335, 924–930.
ffworks.com/animal-facts/mad-cow-disease1.htm. Accessed September
Knipe, D.M., Howley, P.M., 2013. Fields Virology, sixth ed. Lippincott Wil- 22, 2018.
liams & Wilkins, Philadelphia. Genetics Home Reference: Prion disease. http://ghr.nlm.nih.gov/condition=
priondisease. Accessed September 22, 2018.
Lee, K.S., Caughey, B., 2007. A simplified recipe for prions. Proc. Natl. National Prion Disease Pathology Surveillance Center, Homepage. www.
Acad. Sci. U S A. 104, 9551–9552. cjdsurveillance.com/. Accessed September 22, 2018.

Manson, J.C., 1999. Understanding transmission of the prion diseases.
Trends. Microbiol. 7, 465–467.

Mercer, R.C., Ma, L., Watts, J.C., et al., 2013. The prion protein modulates
A-type K+ currents mediated by Kv4.2 complexes through dipeptidyl
aminopeptidase-like protein 6. J. Biol. Chem. 288, 37241–37255.

Case Study and Questions 1. What viral neurologic diseases would have been consid-
ered in the differential diagnosis formulated on the basis
A 70-year-old woman complained of severe headaches, of the symptoms described? What other diseases?
appeared dull and apathetic, and had a constant tremor in
the right hand. One month later, she experienced memory 2 . What key features of the postmortem findings were
loss and moments of confusion. The patient’s condition con- characteristic of the diseases caused by prions?
tinued to deteriorate, and at 2 months after onset of symp-
toms, an abnormal electroencephalograph tracing showing 3. What key features distinguish the prion diseases from
periodic biphasic and triphasic slow-wave complexes was conventional neurologic viral diseases?
obtained. By 3 months, the patient was in a coma-like state.
She also had occasional spontaneous clonic twitching of 4. What precautions should the pathologist have taken
the arms and legs and a startle myoclonic jerking response for protection against infection during the postmortem
to a loud noise. The patient died of pneumonia 4 months examination?
after the onset of symptoms. No gross abnormalities were
noted at autopsy. Astrocytic gliosis of the cerebral cortex,
with fibrils and intracellular vacuolation throughout the
cerebral cortex, was seen on microscopic examination.
There was no swelling and no inflammation.

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