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49  •  Orthomyxoviruses 499

Poland, G.A., Jacobson, R.M., Targonski, P.V., 2007. Avian and pandemic Centers for Disease Control and Prevention, 2010. The 2009 H1N1 pan-
influenza: an overview. Vaccine 25, 3057–3061. demic: summary highlights, April 2009-2010. www.cdc.gov/h1n1flu/
cdcresponse.htm. Accessed August 7, 2018.
Richman, D.D., Whitley, R.J., Hayden, F.G., 2009. Clinical Virology, third Centers for Disease Control and Prevention, Seasonal Influenza (flu). www
ed. American Society for Microbiology Press, Washington, DC. .cdc.gov/flu/. Accessed August 7, 2018.
Nguyen, H.H., 2018. Influenza. http://emedicine.medscape.com/arti
Salomon, R., Webster, R.G., 2009. The influenza virus enigma. Cell 136, cle/219557-overview. Accessed August 7, 2018.
402–410. National Institute of Allergy and Infectious Disease, Flu (influenza). www.
niaid.nih.gov/topics/flu/Pages/default.aspx. Accessed August 7, 2018.
Sano, K., Ainai, A., Suzuki, T., Hasegawa, H., 2017. The road to a more Webster, R.G., 1998. Influenza: an emerging disease.
effective influenza vaccine: up to date studies and future prospects. Vac- wwwnc.cdc.gov/eid/article/4/3/98-0325_article.htm. Accessed
cine 35, 5388–5395. August 7, 2018.

Strauss, J.M., Strauss, E.G., 2007. Viruses and Human Disease, second ed.
Academic, San Diego.

Webster, R.G., Govorkova, E.A., 2006. H5N1 Influenza, continuing evolu-
tion and spread. N. Engl. J. Med. 355, 2174–2177.

Websites
Centers for Disease Control and Prevention, Bourbon virus. www.cdc.gov/

ncezid/dvbd/bourbon/. Accessed August 7, 2018.

Case Study and Questions 3 . Oseltamivir is effective against influenza. What is its
mechanism of action? Will it be effective for this patient?
In late December, a 22-year-old man suddenly experienced For uninfected family members or contacts?
headache, myalgia, malaise, dry cough, and fever. He basi-
cally felt lousy. After a couple of days, he had a sore throat, 4. When was the patient contagious, and how was the
his cough had worsened, he started to feel nauseated, and virus transmitted?
he began vomiting. Several of his family members had expe-
rienced similar symptoms during the previous 2 weeks. 5. Which types of family members were at greatest risk for
1. In addition to influenza, what other agents could cause serious disease and why?

similar symptoms (differential diagnosis)? 6 . Why is influenza so difficult to control, even when there
2 . How would the diagnosis of influenza be confirmed? is a national vaccination program?

499.e1

50 Rhabdoviruses, Filoviruses,

and Bornaviruses

A 15-year-old girl picked up a bat and was bitten on to speak. This is the only example of a patient sur-
her hand. One month later, she developed double viving without having received timely postexposure
vision, nausea, and vomiting. Over the course of rabies immunization1*
4 days, her neurologic disease developed, and she 1 . How is rabies infection confirmed?
had a fever of 38.9° C. Rabies was suspected, and 2 . What is the usual disease progression after a bite from a
rabies virus–specific antibodies were detected in the
patient’s serum and cerebrospinal fluid (1:32 titer). rabid animal?
The patient was put into a drug-induced coma with 3 . When is antirabies antibody detected in a normal rabies
ventilator support and treated with intravenous rib-
avirin for 7 days, when cerebrospinal fluid antibody disease presentation?
titers rose to 1:2048. After 3 months, she was able 4. What is postexposure rabies immunization, and why
to walk with assistance, ride a stationary cycle for 8
minutes, feed herself a soft solid diet, solve math puz- does it work?
zles, use sign language, and was regaining the ability 5. How does ribavirin inhibit the replication of rabies and

other viruses?

 Answers to these questions are available on Student
Consult.com.

Summaries Clinically Significant Organisms

RHABDOVIRUSES ᑏᑏ Antibody can block disease Diagnosis
ᑏᑏ Virus spreads along neurons to salivary ᑏᑏ RT-PCR, antigen detection in biopsy,
Trigger Words
glands and brain presence of Negri bodies in infected cells
Mad dog, hydrophobia, salivation, ᑏᑏ Antibody produced after virus reaches
b­ ullet-shaped virion, Negri bodies Treatment, Prevention, and Control
brain
Biology, Virulence, and Disease ᑏᑏ Incubation period depends on proximity ᑏᑏ Immunization with killed vaccine after
bite and antirabies immunoglobulin
ᑏᑏ Medium size, bullet shaped, enveloped, of bite to CNS and infectious dose
(−) RNA genome ᑏᑏ Prophylaxis if job-related risk
Epidemiology ᑏᑏ Inactivated vaccine for pets
ᑏᑏ Encodes RNA-dependent RNA ᑏᑏ Vaccinia virus hybrid vaccine for wild
­polymerase, replicates in ᑏᑏ Zoonosis
cytoplasm ᑏᑏ Reservoir in skunks, raccoons, foxes, animals

badgers, bats (aerosols)

CNS, Central nervous system; RT-PCR, reverse transcriptase-polymerase chain reaction.

Rhabdoviruses with a diameter of 50 to 95 nm and length of 130 to 380
nm (Fig. 50.1; Box 50.1). Spikes composed of a trimer of
Members of the family Rhabdoviridae (from the Greek word the glycoprotein (G) cover the surface of the virus. The viral
rhabdos, meaning “rod”) include pathogens for a variety attachment protein, G-protein, generates neutralizing anti-
of mammals, fish, birds, and plants. The family contains bodies. The G-protein of the VSV is a simple glycoprotein
Vesiculovirus (vesicular stomatitis viruses [VSVs]), Lyssavi- with N-linked glycan. This G-protein was used as the proto-
rus (Greek for “frenzy”) (rabies and rabies-like viruses), and type for studying eukaryotic glycoprotein processing.
many other rhabdoviruses of plants, mammals, birds, fish,
and arthropods. Within the envelope, the helical nucleocapsid is
coiled symmetrically into a cylindrical structure, giving it
Rabies virus is the most significant pathogen of the rhab- the appearance of striations (see Fig. 50.1). The nucleo-
doviruses. Until Louis Pasteur developed the killed-rabies capsid is composed of one molecule of single-stranded,
vaccine, a bite from a “mad” dog always led to the charac- negative-sense ribonucleic acid (RNA) of approxi-
teristic symptoms of hydrophobia and certain death. mately 12,000 bases and the nucleoprotein (N), large (L),
and nonstructural (NS) proteins. The L and NS proteins
PHYSIOLOGY, STRUCTURE, AND REPLICATION constitute the RNA-dependent RNA polymerase. The N
Rhabdoviruses are simple viruses, encoding only five pro- protein is the major structural protein of the virus. It pro-
teins and appearing as bullet-shaped enveloped virions tects the RNA from ribonuclease digestion and maintains
the RNA in a configuration acceptable for transcription.
1Adapted from Centers for Disease Control and Prevention, 2004. Recov- The matrix (M) protein lies between the envelope and the
ery of a patient from clinical rabies—Wisconsin, 2004, MMWR Morb. nucleocapsid.
Mortal. Wkly. Rep. 53:1171–1173.
The replicative cycle of VSV is the prototype for the
500 rhabdoviruses and other negative-strand RNA viruses

50  •  Rhabdoviruses, Filoviruses, and Bornaviruses 501

Fig. 50.1  Rhabdoviridae seen by electron microscopy: rabies virus BOX 50.2  Disease Mechanisms of Rabies
(left) and vesicular stomatitis virus (right). (From Fields, B.N., 1985. Virol- Virus
ogy. Raven, New York, NY.)
Rabies is usually transmitted in saliva and acquired from the bite
BOX 50.1  Unique Features of Rhabdoviruses of a rabid animal.

Bullet-shaped, enveloped, negative-sense, single-stranded RNA Rabies virus is not very cytolytic and seems to remain cell associ-
viruses that encode five proteins. ated except in salivary gland.

Prototype for replication of negative-strand enveloped viruses. Virus replicates in the muscle at the site of the bite, with minimal
Replication in cytoplasm. or no symptoms (incubation phase).

(see Fig. 36.13). The viral G-protein attaches to the host The length of the incubation phase is determined by the infec-
cell and virions are internalized by endocytosis. Rabies tious dose and the proximity of the infection site to the CNS
virus binds to either the nicotinic acetylcholine recep- and brain.
tor (AChR), neural cell adhesion molecule (NCAM), or
other molecules. The viral envelope then fuses with the After weeks to months, the virus infects the peripheral nerves and
membrane of the endosome on acidification of the vesi- travels up the CNS to the brain (prodrome phase).
cle. This uncoats the nucleocapsid, releasing it into the
cytoplasm, where replication takes place. In neurons, Infection of the brain causes classic symptoms, coma, and death
Endosomal vesicles may deliver whole rabies virions (neurologic phase).
along the axon to neuronal cell to facilitate neuronal
spread. During the neurologic phase, the virus spreads to the glands, skin,
and other body parts, including the salivary glands.
The RNA-dependent RNA polymerase associated with
the nucleocapsid transcribes the viral genomic RNA, pro- Rabies infection does not elicit an antibody response until the late
ducing five individual messenger RNAs (mRNAs). For stages of the disease, when the virus has spread from the CNS
rabies virus, this occurs in the Negri bodies. These mRNAs to other sites.
are then translated into the five viral proteins. The viral
genomic RNA is also transcribed into a full-length, pos- Salivary glands produce and release large amounts of virus and is
itive-sense RNA template that is used to generate new the major source of contagion.
genomes. The G-protein is synthesized by membrane-
bound ribosomes, processed by the Golgi apparatus, Administration of antibody can block progression of the virus and
and delivered to the cell surface in membrane vesicles. disease if given early enough.
The M protein associates with the G-protein–modified
membranes. The long incubation period allows active immunization as a post-
exposure treatment.
Assembly of the virion occurs in two phases: (1) assem-
bly of the nucleocapsid in the cytoplasm and (2) envelop- CNS, Central nervous sy stem.
ment and release at cytoplasmic or plasma membranes.
The genome associates with the N protein and then with PATHOGENESIS AND IMMUNITY
the polymerase proteins L and NS to form the nucleocap-
sid. Association of the nucleocapsid with the M protein Rabies infection usually results from the bite of a rabid
induces coiling into its condensed form and the charac- animal (Box 50.2). Rabies infection of the animal causes
teristic bullet shape of the virion. In most cells, the virus secretion of the virus in the animal’s saliva and promotes
buds from intracytoplasmic membranes and release is aggressive behavior and biting (mad dog), which in turn
inefficient. The exception is the salivary gland, in which promotes transmission of the virus. The virus can also be
the virus buds efficiently from the plasma membrane and transmitted through inhalation of aerosolized virus (as
is released when the entire nucleocapsid is enveloped. The may be found in bat caves), in transplanted infected tissue
time for a single cycle of replication depends on the cell (e.g., cornea), and by inoculation through intact mucosal
type and the inoculum size.  membranes.

The virus replicates quietly at the site of infection for days
to months (Fig. 50.2) before progressing to the peripheral
nervous system and then the central nervous system (CNS).
Rabies virus travels by retrograde axoplasmic transport to
the dorsal root ganglia and the spinal cord. Once the virus
gains access to the spinal cord, the brain becomes rapidly
infected and virus production increases. The affected areas
are the hippocampus, brainstem, ganglionic cells of the
pontine nuclei, and Purkinje cells of the cerebellum. The
virus then disseminates from the CNS via afferent neurons
to highly innervated sites such as the skin of the head and
neck, salivary glands, retina, cornea, nasal mucosa, adre-
nal medulla, renal parenchyma, and pancreatic acinar
cells. Virus is released efficiently from the salivary gland to
promote contagion from infected animals. After the virus
invades the brain and spinal cord, encephalitis develops
and neurons degenerate. Despite extensive CNS involve-
ment and impairment of CNS function, little histopatho-
logic change can be observed in the affected tissue, other
than the presence of Negri bodies (see section on Laboratory
Diagnosis for rhabies).

Rabies is fatal once the clinical disease is apparent.
The length of the incubation period is determined by the

502 SECTION 5  •  Virology 7 Infection of spinal cord, BOX 50.3  Epidemiology of Rabies Virus
brainstem, cerebellum,
8 Descending infection via and other brain structures Disease/Viral Factors
nervous system to eye,
salivary glands, skin, Virus-induced aggressive behavior in animals promotes virus
and other organs spread.

6 Rapid ascent in Production of virus by salivary gland transmits virus in bite.
spinal cord Disease has long, asymptomatic incubation period. 

5 Replication in Transmission
dorsal ganglion
Zoonosis
3 Virion enters peripheral 4 Reservoir: wild animals.
nervous system Passive ascent via Vector: wild animals and unvaccinated dogs and cats.
sensory fibers
Source of virus
1 Virus Major: saliva in bite of rabid animal (including bats).
inoculated Minor: aerosols in bat caves containing rabid bats.
Rare: transplant of contaminated cornea or organ. 
2 Viral replication
in muscle Who Is at Risk?

Veterinarians and animal handlers.
Person bitten by a rabid animal.
Inhabitants of countries with no pet vaccination program. 

Geography/Season

Virus found worldwide, except in some island nations.
No seasonal incidence. 

Modes of Control

Vaccination program is available for pets.
Vaccination is available for at-risk personnel.
Vaccination programs have been implemented to control rabies

in forest mammals.

Fig. 50.2  Pathogenesis of rabies virus infection. Numbered steps maintained and spread in three ways. In urban rabies, dogs
describe the sequence of events. (Modified from Belshe, R.B., 1991. Text- are the primary transmitter, in sylvatic (forest) rabies, many
book of Human Virology, second ed. Mosby, St Louis, MO.) species of wildlife can serve as transmitters, and then there
is bat rabies. Virus-containing aerosols, bites, and scratches
(1) concentration of the virus in the inoculum, (2) proxim- from infected bats also spread the disease. In the United
ity of the wound to the brain, (3) severity of the wound, (4) States, rabies is more prevalent in cats because they are not
host’s age, and (5) host’s immune status. vaccinated. The principal reservoir for rabies in most of the
world, however, is the dog. In Latin America and Asia, this
In contrast to other viral encephalitis syndromes, rabies feature is a problem because of the existence of many stray
is minimally cytolytic and rarely causes inflammatory unvaccinated dogs and the absence of rabies-control pro-
lesions. Viral proteins inhibit apoptosis and aspects of inter- grams. Although rare, there are cases of rabies transmis-
feron action. Little antigen is released, and the infection sion via corneal and organ transplants.
probably remains hidden from the immune response. Neu-
tralizing antibodies are not apparent until after the clinical Because of the excellent dog vaccination program in the
disease is well established. Cell-mediated immunity appears United States, sylvatic and bat exposure accounts for most
to play little or no role in protection against rabies virus of the cases of animal rabies in this country. Statistics for
infection. animal rabies are collected by the Centers for Disease Con-
trol and Prevention, which in 1999 recorded more than
Antibody can block the spread of virus to the CNS and 8000 documented cases of rabies in raccoons, skunks,
brain if administered or generated by vaccination during bats, and farm animals, in addition to dogs and cats (Fig.
the incubation period. The incubation period is usually 50.3). Badgers and foxes are also major carriers of rabies
long enough to allow generation of a therapeutic protective in Western Europe. In South America, vampire bats trans-
antibody response after active immunization with the killed mit rabies to cattle, resulting in losses of millions of dollars
rabies vaccine.  each year.

EPIDEMIOLOGY Although underreported, it is estimated that rabies
Rabies is the classic zoonotic infection spread from ani- accounts for 40,000 to 100,000 deaths (mostly children)
mals to humans (Box 50.3). Rabies occurs in most parts of annually worldwide, with at least 20,000 deaths in India,
the world but is rarely seen in Japan, Australia, New Zea- in which the virus is transmitted by dogs in 96% of cases.
land, United Kingdom, and certain island states. Rabies is In Latin America, cases of human rabies primarily result
from contact with rabid dogs in urban areas. In Indonesia,
an outbreak of more than 200 human cases of rabies in

50  •  Rhabdoviruses, Filoviruses, and Bornaviruses 503

Percent BOX 50.4  Clinical Summary

80 Rabies: A 3-year-old girl was found to have a bat flying in her
bedroom. The bat apparently was there all night. There was no
70 evidence of any bite wound or contact, and the bat was caught
and released. Three weeks later, the child developed a change
60 Raccoon in behavior, becoming irritable and agitated. This state quickly
Skunk 40.6 progressed to confusion, uncontrollable thrashing about, and
50 inability to handle her secretions. She eventually became coma-
40 tose and died from respiratory arrest.
30 29.4
20 Bat Fox Other wild (15% to 60% of patients) may be the only manifestation of
10 14 5.4 animals rabies and may lead to respiratory failure.
2.1
The patient becomes comatose after the neurologic
Wild animals phase, which lasts from 2 to 10 days. This phase almost
universally leads to death resulting from neurologic and
80 pulmonary complications. 

70 LABORATORY DIAGNOSIS
The occurrence of neurologic symptoms in a person who has
60 been bitten by an animal generally establishes the diagnosis
of rabies. Unfortunately, evidence of infection, including symp-
50 toms and the detection of antibody, does not occur until it is too
late for intervention. Laboratory tests are usually performed to
40 confirm the diagnosis (too late for treatment) and determine
whether a suspected animal is rabid (postmortem).
30 Other
domestic Antigen detection using direct immunofluorescence or
20 Cat animals genome detection using reverse transcriptase polymerase
3.9 chain reaction (RT-PCR) are relatively quick and sensitive
10 Dog Cattle 1.2 assays, and they are the preferred methods for diagnosing
1.6 1.9 rabies. Samples of saliva are easy to test, but serum, spinal
fluid, skin biopsy material from the nape of the neck, brain
Domestic animals biopsy or autopsy material, and impression smears of cor-
neal epithelial cells can also be examined.
Fig. 50.3  Distribution of animal rabies in the United States, 1999.
Percentages relate to the total number of cases of animal rabies. (Data Infected cells will have intracytoplasmic inclusions con-
from Krebs, J.W., Rupprecht, C.E., Childs, J.E., 2000. Rabies surveillance in sisting of aggregates of viral nucleocapsids (Negri bodies)
the United States during 1999. Am. Veter. Med. Assoc. 217, 1799–1811.) in affected neurons (see Fig. 39.3). Although their finding
is diagnostic of rabies, Negri bodies are seen in only 70% to
1999 prompted the killing of more than 40,000 dogs on the 90% of brain tissue from infected humans.
islands. The incidence of human rabies in the United States
is approximately one case per year, due in large part to Antibody is not detectable until late in the disease but can
effective dog vaccination programs and limited human con- be assayed from serum and cerebrospinal fluid by enzyme-
tact with skunks, raccoons, and bats. Since 1990, human linked immunosorbent assay (ELISA). 
cases of rabies in the United States are acquired elsewhere
or caused primarily by bat variants of the virus. The World TREATMENT AND PROPHYLAXIS
Health Organization estimates that 10 million people per Clinical rabies is almost always fatal unless treated early
year receive treatment after exposure to animals suspected with postrabies immunization. Once the symptoms have
of being rabid.  appeared, little other than supportive care can be given.
There is one case of successful cessation of disease progres-
CLINICAL SYNDROMES sion by postexposure ribavirin treatment (see introductory
Rabies is virtually always fatal unless treated by vaccina- case study).
tion. After a long but highly variable incubation period, the
prodrome phase of rabies ensues (Box 50.4; Table 50.1). Postexposure prophylaxis is the only hope for prevent-
The patient has symptoms such as fever, malaise, head- ing overt clinical illness in the affected person. Although
ache, pain or paresthesia (itching) at the site of the bite, human cases of rabies are rare, approximately 20,000
gastrointestinal symptoms, fatigue, and anorexia. The pro- people receive rabies prophylaxis each year in the United
drome usually lasts 2 to 10 days, after which the neurologic States alone. Prophylaxis should be initiated for anyone
symptoms specific to rabies appear. Hydrophobia (fear of exposed by bite or by contamination of an open wound or
water), the most characteristic symptom of rabies, occurs mucous membrane to the saliva or brain tissue of an animal
in 20% to 50% of patients. It is triggered by the pain asso- suspected to be infected with the virus, unless the animal is
ciated with the patient’s attempts to swallow water. Focal tested and shown not to be rabid.
and generalized seizures, disorientation, and hallucinations
are also common during the neurologic phase. Paralysis

504 SECTION 5  •  Virology

TABLE 50.1  Progression of Rabies Disease

Disease Phase Symptoms Time (Days) Viral Status Immunologic Status
60–365 after bite
Incubation phase Asymptomatic 2–10 Low titer, virus in muscle —
Prodrome phase —
Fever, nausea, vomiting, loss of appetite, 2–7 Low titer, virus in CNS and
headache, lethargy, pain at site of bite brain

Neurologic phase Hydrophobia, pharyngeal spasms, High titer, virus in brain and Detectable antibody in
­hyperactivity, anxiety, depression
other sites serum and CNS
CNS symptoms: loss of coordination,
p­ aralysis, confusion, delirium

Coma Coma, hypotension, hypoventilation, 0–14 High titer, virus in brain and —
s­ econdary infections, cardiac arrest — other sites

Death — ——

CNS, Central nervous system.

The first protective measure is local treatment of the Fig. 50.4  Electron micrograph of Ebola virus. (Courtesy Centers for Dis-
wound. The wound should be washed immediately with soap ease Control and Prevention, Atlanta, GA.)
and water or another substance that inactivates the virus.
Antirabies immunoglobulin is injected near the wound. in Gabon in 1996, and also after the release of the movie
Outbreak, based on the book by Robin Cook, and the book
Subsequently, four immunizations with rabies vaccine The Hot Zone by Richard Preston. In 2014, an epidemic of
are administered within 2 weeks, with one initial dose of Ebola killed many thousands, mostly in the West African
human rabies immunoglobulin (HRIG) or equine antirabies countries of Liberia, Sierra Leone, and Guinea, and more
serum. Passive immunization with HRIG provides antibody recent outbreaks (2018- ongoing as of printing) have been
until the patient produces antibody in response to the vac- in the Democratic Republic of Congo.
cine. The slow course of rabies disease allows active immu-
nity to be generated in time to afford protection. STRUCTURE AND REPLICATION
Filoviruses have a single-stranded RNA genome (4.5 ×
The rabies vaccine is a killed-virus vaccine prepared 106 Da) that encodes seven proteins. The virions form long
through chemical inactivation of rabies infected–tissue enveloped filaments with a diameter of 80 nm but may also
culture human diploid cells (HDCV) or chick embryo cells. assume other shapes. They vary in length from 800 nm to
These vaccines cause fewer negative reactions than the as long as 1400 nm and may contain none, one, or mul-
older vaccines (Semple and Fermi), which were prepared in tiple genomes. The nucleocapsid is helical and enclosed in
the brains of adult or suckling animals. Serum monitoring an envelope containing one glycoprotein. The glycopro-
and preexposure vaccination should be performed on ani- tein is cleaved into two components, and a shorter ver-
mal workers, laboratory workers who handle potentially sion is secreted. The Ebola virus binds to Niemann-Pick C1
infected tissue, and people traveling to areas in which rabies (NPC1), which is a cholesterol transfer protein, and T-cell
is endemic. HDCV is administered intramuscularly to these immunoglobulin and mucin domain 1 (TIM-1), which is
individuals and provides 2 years of protection. also the hepatitis A virus receptor. The virus enters the cell
and replicates in the cytoplasm like the rhabdoviruses. 
Ultimately, the prevention of human rabies hinges on
effective control of rabies in domestic and wild animals. Its PATHOGENESIS
control in domestic animals depends on removal of stray The filoviruses replicate efficiently, producing large amounts
and unwanted animals and vaccination of all dogs and cats. of virus in endothelial cells, monocytes, macrophage,
A variety of attenuated oral vaccines have also been used
successfully to immunize foxes. A live recombinant vac-
cinia virus vaccine expressing the rabies virus G-protein is
in use in the United States. This vaccine, which is injected
into bait and parachuted into the forest, successfully immu-
nizes raccoons, foxes, and other animals. Accidental injec-
tion of a woman with this vaccinia-rabies hybrid vaccine
resulted in immunization against both smallpox and rabies
viruses (see Bibliography). 

Filoviruses

The Marburg and Ebola viruses (Fig. 50.4) were classi-
fied as members of the family Rhabdoviridae but are now
classified as filoviruses (Filoviridae). They are filamen-
tous, enveloped, negative-strand RNA viruses. These
agents cause severe or fatal hemorrhagic fevers and
are endemic in Africa. Awareness of the Ebola virus
increased after an outbreak of the disease in Zaire in 1995,

50  •  Rhabdoviruses, Filoviruses, and Bornaviruses 505

dendritic cells, and other cells. Replication in macrophages, analysis and in fluids by ELISA. RT-PCR amplification of the
monocytes, and dendritic cells elicits a cytokine storm viral genome in secretions can be used to confirm the diag-
of proinflammatory cytokines similar to a superantigen- nosis and minimize handling of samples. 
induced cytokine storm promoting sepsis-like symptoms.
Viral cytopathogenesis causes extensive tissue necrosis in TREATMENT, PREVENTION, AND CONTROL
parenchymal cells of the liver, spleen, lymph nodes, and Antibody-containing serum, artificially produced antibody
lungs. Infection of endothelial cells prevents production of (ZMAPP), and interferon and ribavirin therapies have been
cell adhesion proteins and causes cytolysis leading to vas- tried in patients with filovirus infections. Infected patients
cular injury and leakage. Strains with mutations in the gly- should be quarantined, and contaminated animals should be
coprotein gene lack the hemorrhagic component of disease. sacrificed. Handling of the viruses, infected individuals, dead
The widespread hemorrhage that occurs in affected patients bodies, and contaminated materials requires very stringent
causes edema, hypovolemic shock, and disseminated intra- (level 4) isolation procedures. Several approaches have been
vascular coagulopathy (DIC). The virus also can evade host used to develop a vaccine. In the 2018 outbreak in the Demo-
innate, including interferon, and immune responses.  cratic Republic of Congo, the rVSV-ZEBOV, a recombinant
vaccine in which VSV expresses the Ebola glycoprotein instead
EPIDEMIOLOGY of its own, was used. Health care workers and individuals in
Marburg virus infection was first detected among labora- areas surrounding the outbreak of Ebola who are most likely
tory workers in Marburg, Germany, who had been exposed to be infected (ring vaccination) had priority to be immunized. 
to tissues from apparently healthy African green monkeys.
Rare cases of Marburg virus infection have been seen in Borna Disease Virus
Zimbabwe and Kenya.
Borna disease virus (BDV) is the only member of a fam-
Ebola virus was named for the river in the Democratic ily of enveloped, negative-strand RNA viruses. BDV was
Republic of Congo (formerly Zaire) in which it was discovered. first associated with infection of horses in Germany. The
Outbreaks of Ebola virus disease have occurred in the Demo- virus has received considerable interest because of its asso-
cratic Republic of Congo, Sudan, and, most recently, Liberia, ciation with specific neuropsychiatric diseases such as
Sierra Leone, and Guinea. During an outbreak, the Ebola schizophrenia.
virus is so lethal it can eliminate the susceptible population
before it can be spread from the region. In urban areas, spread STRUCTURE AND REPLICATION
of the virus is more difficult to control. In rural areas of central The 8910-nucleotide-long genome of BDV encodes five
Africa, as much as 18% of the population has antibody to this detectable proteins, including a polymerase (L), nucleoprotein
virus, indicating that subclinical infections do occur. (N), phosphoprotein (P), matrix protein (M), and envelope
glycoprotein (G). Unlike most negative-strand viruses, BDV
These viruses may be endemic in bats or wild monkeys and replicates in the nucleus. Although this is similar to the ortho-
can be spread to humans and between humans. Contact with myxoviruses, BDV differs in that its genome is unsegmented. 
the animal reservoir or direct contact with infected blood or
secretions can spread the disease. These viruses have been PATHOGENESIS
transmitted by accidental injection and through the use of BDV is highly neurotropic and capable of spreading through-
contaminated syringes. Health care workers tending to the out the CNS. BDV also infects parenchymal cells of different
sick, funeral workers, and monkey handlers may be at risk. In organs and peripheral blood mononuclear cells. The virus
response to the 2014 epidemic, screening similar to that for is not very cytolytic and establishes a persistent infection in
severe acute respiratory syndrome (SARS) coronavirus was the infected individual. T-cell immune responses are impor-
initiated at major airports, and all patients in the United States tant for controlling BDV infections but also contribute to tis-
with flulike symptoms were asked for their travel history.  sue damage, leading to disease. 

CLINICAL SYNDROMES CLINICAL SYNDROMES
Marburg and Ebola viruses (Clinical Case 50.1) are the most Although there is limited understanding of the BDV disease
severe causes of viral hemorrhagic fevers. The illness usu- in humans, infection of animals can result in subtle losses of
ally begins with flulike symptoms such as headache and learning and memory and in fatal immune-mediated menin-
myalgia. Nausea, vomiting, and diarrhea occur within a goencephalitis. Many of the outcomes of BDV infection of
few days; a rash also may develop. Subsequently, hemor- laboratory animals resemble human neuropsychiatric dis-
rhage from multiple sites (especially the gastrointestinal eases, including depression, bipolar disorder, schizophrenia,
tract) and death occur in as many as 90% of patients with and autism. The presence of antibodies to the virus and/
clinically evident disease.  or infected peripheral blood mononuclear cells in higher
than background numbers of patients with schizophrenia,
LABORATORY DIAGNOSIS autism, and other neuropsychiatric diseases suggests that
All specimens from patients with a suspected filovirus infec- BDV either causes or exacerbates these mental illnesses. 
tion must be handled with extreme care to prevent accidental
infection. Handling of these viruses requires level 4 isola-
tion procedures that are not routinely available. Viral anti-
gens can be detected in tissue by direct immunofluorescence

506 SECTION 5  •  Virology

EPIDEMIOLOGY   For a case study and questions see StudentConsult.com
BDV is capable of infecting many different mammalian
species (zoonosis), including horses, sheep, and humans. Bibliography
Most outbreaks of the virus have occurred in Central
Europe, but it has also been detected in North America Anderson, L.J., Nicholson, T.G., Tauxe, R.V., et al., 1984. Human rabies
and Asia. Neither the reservoir nor the mode of trans- in the United States, 1960–1979: epidemiology, diagnosis, and preven-
mission of BDV is known. Higher levels of infection of tion. Ann. Intern. Med. 100, 728–735.
humans are present where outbreaks in horses have been
observed.  Burrell, C., Howard, C., Murphy, F., 2016. Fenner and White’s Medical
LABORATORY DIAGNOSIS Virology, fifth ed. Academic, New York.
Infection can be detected by direct analysis for the viral
genome and mRNA in peripheral blood mononuclear cells Centers for Disease Control and Prevention, 1988. Rabies vaccine,
using RT-PCR. Serologic analysis of antibody to the viral absorbed: a new rabies vaccine for use in humans. MMWR Morb. Mor-
proteins continues to be used to identify an association of tal. Wkly. Rep. 37, 217–223.
BDV with human diseases. 
TREATMENT Cohen, J., Powderly, W.G., 2004. Infectious Diseases, second ed. Mosby,
Similar to many other RNA viruses, BDV is sensitive to riba- St. Louis.
virin treatment. Ribavirin treatment may be a reasonable
treatment approach for some psychoneurologic disorders if Flint, S.J., Racaniello, V.R., et al., 2015. Principles of Virology, fourth ed.
BDV is demonstrated as a cofactor. American Society for Microbiology Press, Washington, DC.

Clinical Case 50.1 Ebola Knipe, D.M., Howley, P.M., 2013. Fields Virology, sixth ed. Lippincott Wil-
liams & Wilkins, Philadelphia.
Emond and associates described the following case of Ebola
infection (Br Med J 2:541–544, 1977). Within 6 days of a Mandell, G.L., Bennet, J.E., Dolin, R., 2015. Principles and Practice of
needle-stick accident while handling animal liver infected Infectious Diseases, eight ed. Saunders, Philadelphia.
with Ebola virus, a scientist complained of abdominal
pain and nausea. He was transferred to a high-security Plotkin, S.A., 2000. Rabies: state of the art clinical article. Clin. Infect. Dis.
infectious disease unit and placed in an isolation room. At 30, 4–12.
admission (day 1), he was experiencing fatigue, anorexia,
nausea, and abdominal pain and had a fever of 38° C. Richman, D.D., Whitley, R.J., Hayden, F.G., 2017. Clinical Virology,
Interferon was administered twice a day, and it appeared fourth ed. American Society for Microbiology Press, Washington, DC.
to have worked, except that the next morning his fever
returned (39° C). He was given heat-inactivated convales- Rupprecht, C.E., 2001. Human infection due to recombinant vaccinia-
cent serum with no immediate effect. On day 4, he sweated rabies glycoprotein virus. N. Engl. J Med. 345, 582–586.
profusely, and his temperature dropped to normal, but he
had a new rash on his chest. At midday of day 4, he expe- Schnell, M.J., McGettigan, J.P., Wirblich, C., et al., 2010. The cell biology
rienced sudden violent shivering, fever of 40° C, nausea, of rabies virus: using stealth to reach the brain. Nat. Rev. Microbiol. 8,
vomiting, and diarrhea. These symptoms continued for 3 51–61.
days, with spread of the rash across his body. On day 6,
more convalescent serum and rehydration treatment were Steele, J.H., 1988. Rabies in the Americas and remarks on the global
administered. The patient made a slow recovery over the aspects. Rev. Infect. Dis. 10 (Suppl. 4), S585–S597.
next 10 weeks. Virus (detected by electron microscopy and
inoculation of guinea pigs) was present in his blood from Strauss, J.M., Strauss, E.G., 2007. Viruses and Human Disease, second ed.
the first day of symptoms. (Currently, the analysis would Academic, San Diego.
be performed by reverse transcriptase-polymerase chain
reaction, with less risk to laboratory personnel.) Virus Warrell, D.A., Warrell, M.J., 1988. Human rabies and its prevention: an
titers dropped by 1000-fold after interferon treatment and overview. Rev. Infect. Dis. 10 (Suppl. 4), S726–S731.
were undetectable by day 9. Treatment of the patient and
handling of samples were performed under the strictest Winkler, W.G., 1992. Bogel K: Control of rabies in wildlife. Sci. Am. 266, 86–92.
isolation conditions available at the time. Even though the Wunner, W.H., Larson, J.K., Dietzschold, B., et al., 1988. The molecular
scientist took precautions and soaked his hand in bleach
as soon as possible, his fate was already sealed. Luckily, biology of rabies viruses. Rev. Infect. Dis. 10 (Suppl. 4), S771–S784.
interferon therapy and convalescent serum were available
to limit the extent of disease progression. In their absence, Filoviruses
he would have died from a rapidly progressing hemor- Centers for Disease Control and Prevention, Ebola (Ebola virus disease).
rhagic disease
www.cdc.gov/vhf/ebola/. Accessed August 10, 2018.
Groseth, A., Feldmann, H., Strong, J.E., 2007. The ecology of Ebola virus.

Trends. Microbiol. 15, 408–416.
King, J.W., 2018. Ebola. http://emedicine.medscape.com/article/216288-

overview. Accessed August 10, 2018.
Klenk, H.D., 1999. Marburg and Ebola Viruses. Current Topics in Microbi-

ology and Immunology (vol. 235), p. 225.
Mohamadzadeh, M., Chen, L., Schmaljon, A.L., 2007. How Ebola and Mar-

burg viruses battle the immune system. Nat. Rev. Immunol. 7, 556–567.
Preston, R., 1994. The Hot Zone. Random House, New York.
Sodhi, A., 1996. Ebola virus disease. Postgrad. Med. 99, 75–76.

Bornaviruses
Jordan, I., 2001. Lipkin WI: borna disease virus. Rev. Med. Virol. 11, 37–57.
Richt, J.A., et  al., 1997. Borna disease virus infection in animals and

humans. Emerg. Infect. Dis. 3, 129–135. wwwnc.cdc.gov/eid/article/3
/3/pdfs/97-0311.pdf. Accessed August 10, 2018.

Websites
Centers for Disease Control and Prevention, Ebola hemorrhagic fever. ww

w.cdc.gov/vhf/ebola/index.html. Accessed August 10, 2018.
Centers for Disease Control and Prevention, Rabies. www.cdc.gov/rabies/.

www.cdc.gov/features/dsRabies/index.html. Accessed August 10, 2018.
Centers for Disease Control and Prevention, Rabies Vaccines. https://ww

w.cdc.gov/vaccines/vpd/rabies/hcp/index.html. Accessed August 10,
2018.
Gompf, S.G., Pham, T.M., Somboonwit, C., et al., 2017. Rabies. http://emedic
ine.medscape.com/article/220967-overview. Accessed August 10, 2018.
Kapitanyan, R., Pryor II, P.W., Bertolini, J., et al., 2017. Emergency treat-
ment of rabies. http://emedicine.medscape.com/article/785543-over-
view. Accessed August 10, 2018.
King, J.W., Markanday, A., 2018. Ebola virus. http://emedicine.medscape
.com/article/216288-overview. Accessed August 10, 2018.
WHO, Rabies. www.who.int/topics/rabies/en/. Accessed August 10, 2018.

Case Study and Questions boy had been bitten on the finger by a dog while on a trip
to India.
An 11-year-old boy was brought to a hospital in California 1. What clinical features of this case suggested rabies?
after falling; his bruises were treated, and he was released. 2. Why does rabies have such a long incubation period?
The next day, he refused to drink water with his medicine, 3. What treatment should have been given immediately
and he became more anxious. That night he began to act
up and hallucinate. He also was salivating and had diffi- after the dog bite? What treatment should have been
culty breathing. Two days later, he had a fever of 40.8°  C given as soon as the diagnosis was suspected?
(105.4° F) and experienced two episodes of cardiac arrest. 4. How do the clinical aspects of rabies differ from those of
Although rabies was suspected, no remarkable data were other neurologic viral diseases?
obtained from a computed tomographic image of the brain
or cerebrospinal fluid analysis. A skin biopsy from the nape
of the neck was negative for viral antigen on day 3 but posi-
tive for rabies on day 7. The patient’s condition continued
to deteriorate, and he died 11 days later. When the parents
were questioned, it was learned that 6 months earlier the

506.e1

51 Reoviruses

In January, a 6-month-old boy was seen in the emer- 2. How would the diagnosis of rotavirus have been con-
gency department after 2 days of persistent watery firmed?
diarrhea and vomiting accompanied by a low-grade
fever and mild cough. The infant appeared dehy- 3 . How was the virus transmitted? How long was the
drated and required hospitalization. The patient patient contagious?
attended a day-care center.
1. In addition to rotavirus, what other viral agents must 4 . Who was at risk for serious disease?

be considered in the differential diagnosis of this infant’s  Answers to these questions are available on Student
disease? What agents would need consideration if the Consult.com.
patient were a teenager or an adult?

Summaries Clinically Significant Organisms ᑏᑏ Each segment encodes one or two proteins ᑏᑏ Fecal-oral spread, very contagious,
ᑏᑏ Mixed infection results in genetic mixing infants at risk for serious disease
REOVIRUSES
Trigger Words of segments: reassortment Diagnosis
Fecal-oral, infantile diarrhea, double- ᑏᑏ Rotavirus induces cholera-type diarrhea ᑏᑏ ELISA for virus in stool
ᑏᑏ One of the most serious causes of diarrhea Treatment, Prevention, and Control
double (capsid and double-stranded ᑏᑏ Treatment: supportive rehydration
segmented RNA genome), oral vaccine in young children ᑏᑏ Prevention: oral live vaccines adminis-
ᑏᑏ Colorado tick fever, zoonosis, dengue-like
Biology, Virulence, and Disease tered at 2, 4, and 6 months of age
ᑏᑏ Medium size, double capsid, double- disease with rash ᑏᑏ Control: handwashing and good

stranded segmented RNA genome Epidemiology hygiene
ᑏᑏ Capsid resistant to inactivation
ᑏᑏ Encodes RNA-dependent RNA ᑏᑏ Rotavirus
ᑏᑏ Worldwide and ubiquitous, occurs year
­polymerase, replicates in cytoplasm
round

The Reoviridae consist of the orthoreoviruses, rotaviruses, Structure
orbiviruses, and coltiviruses (Table 51.1). The name reovirus
was proposed in 1959 by Albert Sabin for a group of respiratory Rotaviruses and reoviruses share many structural, rep-
and enteric viruses that were not associated with any known licative, and pathogenic features. Reoviruses and rotavi-
disease (respiratory, enteric, orphan). The Reoviridae are ruses have an icosahedral morphology with a double or
nonenveloped viruses with double-layered protein capsids triple protein-layered capsid (60 to 80 nm in diameter) (Fig.
containing 10 to 12 segments of the double-stranded 51.1; Box 51.1) and a double-stranded segmented genome.
ribonucleic acid (dsRNA) genomes. These viruses are sta- The name rotavirus is derived from the Latin word rota,
ble in detergents, over wide pH and temperature ranges, and in meaning “wheel,” which refers to the triple-layered virion
airborne aerosols. The orbiviruses and coltiviruses are spread appearance in negative-stained electron micrographs (Fig.
by arthropods and are arboviruses. 51.2). Proteolytic cleavage of the outer capsid (as occurs in
the gastrointestinal tract) activates the virus for infection
The orthoreoviruses, also referred to as mammalian and produces an intermediate/infectious subviral par-
reoviruses or simply reoviruses, were first isolated in the ticle (ISVP).
1950s from the stools of children. They are the prototype of
this virus family, and the molecular basis of their pathogen- The outer capsid is composed of structural proteins (Figs.
esis has been studied extensively. In general, these viruses 51.3 and 51.4) that surround a nucleocapsid core that
cause asymptomatic infections in humans. includes enzymes for RNA synthesis and 10 (reovirus) or
11 (rotavirus) different dsRNA genomic segments. For rota-
Rotaviruses cause human infantile gastroenteri- virus, the inner capsid consisting of VP2 is surrounded by
tis, which is a very common disease. Before the use of the the intermediate capsid consisting mainly of the major cap-
rotavirus vaccines, rotaviruses accounted for approxi- sid protein (VP6) and an outer layer that contains the viral
mately 50% of all cases of diarrhea in children requiring attachment protein (VP4) and glycoprotein (VP7). Of inter-
hospitalization because of dehydration and in underde- est, rotaviruses resemble enveloped viruses in that they (1)
veloped countries, accounted for at least 1 million deaths have glycoproteins (VP7, NSP4) that are on the outside
each year from uncontrolled viral diarrhea in undernour- of the virion, (2) acquire but then lose an envelope during
ished children. Fortunately, newer vaccines are safer and
have lessened the incidence of this disease worldwide. 507

508 SECTION 5  •  Virology

assembly, and (3) appear to have a fusion protein activity Replication
that promotes direct penetration of the target cell membrane.
Replication of reoviruses and rotaviruses starts with inges-
The genomic segments of rotaviruses and reoviruses tion of the virus (Fig. 51.5). The virion outer capsid protects
encode structural and nonstructural proteins. As for the the inner nucleocapsid and core from the environment, espe-
influenza virus, reassortment of gene segments can occur cially the acidic environment of the gastrointestinal tract. The
and thus create hybrid viruses. The genomic segments of complete virion is then partially digested in the gastrointes-
rotavirus, the proteins they encode, and their functions tinal tract and activated by protease cleavage and loss of the
are summarized in Table 51.2, and those of the reovirus external capsid proteins (σ3/VP7) and cleavage of the σ1/
are summarized in Table 51.3. Core proteins include enzy- VP4 protein to produce the ISVP. The σ1/VP4 protein at the
matic activities required for the transcription of messenger vertices of the ISVP binds to sialic acid–containing glycopro-
RNA (mRNA). They include a 5′-methyl guanosine mRNA teins on epithelial and other cells. Additional receptors include
capping enzyme and an RNA polymerase. The σ1 protein the β-adrenergic receptor for reovirus and integrin molecules
(reovirus) and VP4 (rotavirus) are located at the vertices of for rotavirus. The cleaved VP4 of rotavirus also promotes the
the capsid and extend from the surface like spike proteins. direct penetration of the virion through the plasma membrane
They have several functions, including viral attachment into the cell. Whole virions of reovirus and rotavirus can also
and hemagglutination, and they elicit neutralizing antibod- be taken up by receptor-mediated endocytosis.
ies. VP4 is activated by protease cleavage into VP5 and VP8
proteins, exposing a structure similar to that of the fusion The ISVP releases the core into the cytoplasm, and the
proteins of paramyxoviruses. Its cleavage facilitates pro- enzymes in the core initiate mRNA production. The dsRNA
ductive entry of the virus into cells.  always remains in the core. Transcription of the genome
occurs in two phases, early and late. In a manner similar to
TABLE 51.1  Reoviridae Responsible for Human Disease a negative-sense RNA virus, each of the negative-sense (−)
RNA strands is used as a template by virion core enzymes,
Virus Disease which synthesize individual mRNAs. Virus-encoded
Orthoreovirusa enzymes within the core add a 5′-methyl guanosine cap and
Orbivirus/Coltivirus Mild upper respiratory tract illness, gastrointes- a 3′-polyadenylate tail. The 5′-methyl guanosine cap was
tinal tract illness, biliary atresia first discovered for reovirus mRNA and then shown to occur
Rotavirus for cellular mRNA. The mRNA then leaves the core and is
Febrile illness with headache and myalgia translated. Later, virion proteins and positive-sense (+) RNA
(zoonosis) segments associate together into corelike structures within
large cytoplasmic inclusions called viroplasms. The (+) RNA
Gastrointestinal tract illness, respiratory tract segments are copied to produce (−) RNAs in the new cores,
illness (?)

aReovirus is the common name for the family Reoviridae and for the specific
genus Orthoreovirus.

Fig. 51.1  Computer reconstruction of cryoelectron micrographs of human reovirus type 1 (Lang). Top, left to right: Cross section of virion, intermediate/
infectious subviral particle (ISVP), and core particle. The ISVP and core particles are generated by proteolysis of the virion and play important roles in the
replication cycle. Center and bottom: Computer-generated images of the virions at different radii after the outer layers of features have been shaved off.
The colors help one visualize the symmetry and molecular interactions within the capsid. (Courtesy Tim Baker, Purdue University, West Lafayette, Indiana.)

51  •  Reoviruses 509

BOX 51.1  Unique Features of Reoviridae dsRNA segment

Double-layered or triple-layered capsid virion (60 to 80 nm) VPI/VP3
has icosahedral symmetry containing 10 to 12 (depending VP2
on the virus) unique double-stranded genomic segments
(double:double virus). VP6
VP7
Virion is resistant to environmental and gastrointestinal condi-
tions (e.g., detergents, acidic pH, drying). VP4

Rotavirus and orthoreovirus virions are activated by mild proteoly-
sis to intermediate/infectious subviral particles, increasing their
infectivity.

Inner capsid contains a complete transcription system, including
RNA-dependent RNA polymerase and enzymes for 5′ capping
and polyadenylate addition.

Viral replication occurs in the cytoplasm. Double-stranded RNA
remains in the inner core.

Inner capsid aggregates around (+) RNA and transcribes (−) RNA
in the cytoplasm.

Rotavirus-filled inner capsids bud into the endoplasmic reticulum,
acquiring its outer capsid and a membrane, which is then lost.

Virus is released by cell lysis.

Fig. 51.3  Schematic of rotavirus. See Table 51.2 for descriptions of the
viral proteins. dsRNA, Double-stranded ribonucleic acid.

Reovirus/rotavirus
Outer capsid
Core
σ3/VP7

σ1/VP4
λ2/VP6 core
spike

µ1C

Fig. 51.2  Electron micrograph of rotavirus. Bar = 100 nm. (From Fields, Fig. 51.4  Structure of rotavirus core and outer proteins. See Table
B.N., Knipe, D.M., Chanock, R.M., et al., 1985. Virology. Raven, New York.) 51.2 for descriptions of the viral proteins. (Modified from Sharpe, A.H.,
Fields, B.N., 1985. Pathogenesis of viral infections. Basic concepts derived
replicating the double-stranded genome. The new cores from the reovirus model. N. Engl. J. Med. 312, 486–497.)
either generate more (+) RNA or are assembled into virions.
gastroenteritis-causing viruses infecting many different
The assembly processes for reovirus and rotavirus differ. mammals and birds.
In the assembly of reovirus, the outer capsid proteins associ-
ate with the core, and the virion leaves the cell on cell lysis. Rotavirus virions are stable to environmental abuse,
Assembly of rotavirus resembles that of an enveloped virus including treatment with detergents, pH extremes of 3.5
in that the rotavirus cores associate with the NSP4 viral to 10, and even repeated freezing and thawing. Within
protein on the outside of the endoplasmic reticulum (ER); the intestine, proteolytic enzymes such as trypsin enhance
on budding into the ER, they acquire its VP7 outer capsid infectivity.
glycoprotein. The membrane is lost in the ER, and the virus
leaves the cell during cell lysis. Cellular macromolecular Human and animal rotaviruses are divided into sero-
synthesis is inhibited within 8 hours of infection.  types, groups, and subgroups. Serotypes are distinguished
primarily by the VP7 (glycoprotein, G) and VP4 (prote-
Rotaviruses ase-sensitive protein, P) outer capsid proteins. Groups are
determined primarily on the basis of the antigenicity of VP6
Rotaviruses are common agents of infantile diar- and the electrophoretic mobility of the genomic segments.
rhea worldwide. The rotaviruses are a large group of Seven groups (A to G) of human and animal rotaviruses
have been identified on the basis of the VP6 inner capsid
protein. Human disease is caused by group A rotavirus and
occasionally group B and C rotaviruses.

510 SECTION 5  •  Virology

TABLE 51.2  Functions of Rotavirus Gene Products

Gene Segment Protein (Location) Function
1 VP1 (inner capsid)
2 VP2 (inner capsid) Polymerase
3 VP3 (inner capsid) Transcriptase component
4 VP4 (outer capsid spike protein at
mRNA capping
5 vertices of virion)
6 NSP1 (NS53) Activation by protease produces VP5 and VP8 in ISVP, hemagglutinin, viral attachment
VP6 (inner capsid) proteina
7
8 NSP3 (NS34) RNA binding
9 NSP2 (NS35)
VP7 (outer capsid) Major structural protein of inner capsid, binding to NSP4 at ER to promote assembly of
10 outer capsid
NSP4 (NS28)
11 RNA binding
11 NSP5 (NS26)
NSP6 RNA binding, important for genome replication and packaging

Type-specific antigen, major outer capsid component that is glycosylated in ER and
facilitates attachment and entrya

Glycosylated protein in ER that promotes inner capsid binding to ER, transient envelop-
ment, and addition of outer capsid; acts as enterotoxin to mobilize calcium and cause
diarrhea

RNA binding

Binds to NSP5

aTarget of neutralizing antibody.
ER, Endoplasmic reticulum; ISVP, intermediate/infectious subviral particle; mRNA, messenger ribonucleic acid.

TABLE 51.3  Functions of Reovirus Gene Products

Genomic Virion Endoplasmic Nucleus
S­ egments ISVP
(Molecular Protein Function (If Known) reticulum
Weight, Da)
Polymerase Transcription VP7 NSP4
Capping enzyme Translation VP7
LARGE SEGMENTS (2.8 × 106) Transcriptase component Direct (*GmRNAAAA)11 NSP4
1 λ3 (inner capsid)
binds RNA and microtubules penetration
2 λ2 (outer capsid) Cleaved from μ1, complexes Encapsidation Replication Release by
(single shell) Final cell lysis
3 λ1 (inner capsid) with σ3, promotes entry assembly
MEDIUM SEGMENTS (1.4 × 106) Promotes viral assemblya (double
1 μ2 (inner capsid) shell)
Viral attachment protein, Aggregation
hemagglutinin, determines
2 μ1C (outer capsid) tissue tropismb

3 μNS Facilitates viral RNA synthesis Fig. 51.5  Replication of rotavirus. Rotavirus virions can be activated
SMALL SEGMENTS (0.7 × 106) Facilitates viral RNA synthesis by protease (e.g., in the gastrointestinal tract) to produce an inter-
1 σ1 (outer capsid) Major component of outer mediate/infectious subviral particle (ISVP). The virion or ISVP binds,
penetrates the cell, and loses its outer capsid. The inner capsid con-
2 σ2 (inner capsid) capsid with μ1C tains the enzymes for messenger ribonucleic acid (mRNA) transcrip-
3 σNS tion using the (±) strand as a template. Some mRNA segments are
4 σ3 (outer capsid) transcribed early, and others are transcribed later. Enzymes in the
virion cores attach 5′-methyl capped guanosine (*G) and 3′-polyad-
aProteins are not found in the virion. enylate sequence (poly A [AAA]) to mRNA. (+) RNA is mRNA and is
bTarget of neutralizing antibodies. also enclosed into inner capsids as a template to replicate the ± seg-
Modified from Fields, B.N., Knipe, D.M., Howley, P.M., 1996. Virology, third ed. mented genome. VP7 and NSP4 are synthesized as glycoproteins and
expressed in the endoplasmic reticulum. The capsids aggregate and
Lippincott-Raven, New York. “dock” onto the NSP4 protein in the endoplasmic reticulum, acquiring
VP7 and its outer capsid and an envelope. The virus loses the envelope
and leaves the cell on cell lysis.

PATHOGENESIS AND IMMUNITY covering the villi of the small intestine. Approximately
The rotavirus can survive the acidic environment in a 8 hours after infection, cytoplasmic inclusions that con-
buffered stomach or in a stomach after a meal and is con- tain newly synthesized proteins and RNA are seen. As
verted to the ISVP by proteases (Box 51.2). Clumps of the many as 1010 viral particles per gram of stool may be
virus have enhanced infectivity. Viral replication occurs released during disease. Studies of the small intestine,
after adsorption of the ISVP to columnar epithelial cells either of experimentally infected animals or in biopsy
specimens from infants, show shortening and blunting of

51  •  Reoviruses 511

BOX 51.2  Disease Mechanisms of Rotavirus BOX 51.3  Epidemiology of Rotavirus

Virus is spread primarily by the fecal-oral route. Disease/Viral Factors
Cytolytic and toxin-like action on the intestinal epithelium causes Capsid virus is resistant to environmental and gastrointestinal

loss of electrolytes and prevents reabsorption of water. conditions.
Disease can be significant in infants <24 months, but can be Large amounts of virus are released in fecal matter.
Asymptomatic infection can result in release of virus. 
asymptomatic in adults. Transmission
Large amounts of virus are released during the diarrheal phase. Virus is transmitted in fecal matter, especially in day-care settings.
Respiratory transmission may be possible. 
the microvilli and mononuclear cell infiltration into the Who Is at Risk?
lamina propria. Rotavirus Group A
Infants <24 months of age: at risk for infantile gastroenteritis with
Similar to cholera, rotavirus infection prevents absorp-
tion of water, causing a net secretion of water and loss of potential dehydration.
ions, which together result in a watery diarrhea. The NSP4 Older children and adults: at risk for mild diarrhea.
protein of rotavirus acts in a toxin-like manner to pro- Undernourished people in underdeveloped countries: at risk for
mote calcium ion influx into enterocytes, which disrupts the
cytoskeleton and the tight junctions to cause leakage and diarrhea, dehydration, and death. 
also the release of cytokines and neuronal activators, which Rotavirus Group B (Adult Diarrhea Rotavirus)
alter water absorption. The loss of fluids and electrolytes can Infants, older children, and adults in China: at risk for severe
lead to severe dehydration and even death if therapy does
not include electrolyte replacement. Of interest, the diar- gastroenteritis. 
rhea also promotes transmission of the virus. Geography/Season
Virus is found worldwide.
Immunity to infection depends on antibody, primarily Disease is more common in autumn, winter, and spring. 
immunoglobulin (Ig)A, in the lumen of the gut. Antibodies Modes of Control
to the VP7 and VP4 neutralize the virus. Actively or pas- Handwashing and isolation of known cases are modes of control.
sively acquired antibody (including antibody in colostrum Live vaccines use attenuated human or bovine reassorted
and mother’s milk) can lessen the severity of disease but
does not consistently prevent reinfection. In the absence of ­rotavirus.
antibody, the inoculation of even small amounts of virus
causes infection and diarrhea. Infection in infants and small Clinical Case 51.1  Rotavirus Infection
children is generally symptomatic, whereas in adults it is of Adults
usually asymptomatic. 
Mikami and associates (J Med Virol 73:460–464, 2004) de-
EPIDEMIOLOGY scribed an outbreak of acute gastroenteritis that occurred
Rotaviruses are ubiquitous worldwide, with 95% of children over a 5-day period in 45 of 107 children (aged 11 to 12
infected by 3 to 5 years of age (Box 51.3). Rotaviruses are years) after a 3-day school trip. The source person for the
passed from person to person by the fecal-oral route. Maxi- outbreak was ill at the start of the trip. A case of rotavirus
mal shedding of the virus occurs 2 to 5 days after the start acute gastroenteritis is defined as three or more episodes of
of diarrhea but can occur without symptoms. The virus sur- diarrhea and/or two or more episodes of vomiting per day.
vives well on fomites (e.g., furniture and toys) and on hands Other symptoms included fever, nausea, fatigue, abdomi-
because it can withstand drying. Outbreaks occur in pre- nal pain, and headache. The rotavirus responsible for the
schools and day-care centers and among hospitalized infants. outbreak was identified from stool of several individuals as
serotype G2 group A rotavirus compared with the genomic
Rotaviruses are one of the most common causes of ribonucleic acid migration pattern by electrophoresis, by
serious diarrhea in young children worldwide. Before reverse transcriptase-polymerase chain reaction, and by
the vaccines, 4 of 5 children would get rotavirus diar- enzyme-linked immunosorbent assay of virus obtained
rhea and 1 of 7 of them required medical help, with 20 to from stool samples. Although rotavirus is the most com-
50 deaths per year in the United States and as many as mon cause of infantile diarrhea, this virus, especially the
500,000 deaths worldwide. In North America, outbreaks G2 strain, also causes gastroenteritis in adults. This article
occur during the autumn, winter, and spring. More severe illustrated the different laboratory methods available for
disease occurs in severely malnourished children. In devel- detection of a virus that is difficult to grow in tissue culture.
oping countries, rotavirus diarrhea is a very contagious
and severe life-threatening disease for infants and occurs diarrheal illness is estimated to be 48 hours. The major clin-
year round. Several outbreaks of group B rotavirus have ical findings in hospitalized patients are vomiting, diar-
occurred in China because of contaminated water supplies rhea, fever, and dehydration. Neither fecal leukocytes
that affected millions of people.  nor blood occurs in stool for this form of diarrhea. Rotavi-
rus gastroenteritis is a self-limited disease, and recovery is
CLINICAL SYNDROMES generally complete and without sequelae. However, the
Rotavirus is a major cause of gastroenteritis (Clinical
Case 51.1; Box 51.4). The incubation period for rotavirus

512 SECTION 5  •  Virology

BOX 51.4  Clinical Summary Oral administration of these vaccines promotes secretory
IgA production and good memory responses. 
Rotavirus: A 1-year-old infant has watery diarrhea, vomiting, and
fever for 4 days. Enzyme-linked immunosorbent assay analysis Orthoreoviruses (Mammalian
of stool confirms rotavirus. The baby is very dehydrated. Reoviruses)

infection may prove fatal in infants who are malnourished The orthoreoviruses are ubiquitous. The virions are very
and dehydrated before the infection.  stable and have been detected in sewage and river water.
The mammalian reoviruses occur in three serotypes
LABORATORY DIAGNOSIS referred to as reovirus types 1, 2, and 3; these serotypes
The clinical findings in patients with rotavirus infection are based on neutralization and hemagglutination inhibi-
resemble those of other viral diarrheas (e.g., Norwalk virus). tion tests.
Most patients have large quantities of virus in stool, mak-
ing direct detection of viral antigen the method of choice for PATHOGENESIS AND IMMUNITY
diagnosis. Enzyme-linked immunoassay and latex aggluti- Orthoreoviruses do not cause significant disease in humans.
nation are quick, easy, and relatively inexpensive ways to However, studies of reovirus disease in mice have advanced
detect rotavirus in stool. Viral particles in specimens can our understanding of the pathogenesis of viral infections in
also be readily detected on electron microscopy or by immu- humans. Depending on the reovirus strain, the virus can
noelectron microscopy. Reverse transcriptase polymerase be neurotropic or viscerotropic in mice. The functions and
chain reaction (RT-PCR) is useful to detect and distinguish virulence properties of the reovirus proteins were identified
the genotypes of rotavirus. through comparison of the activities of interstrain hybrid
(reassortant) viruses that differ in only one genomic seg-
Cell culture of rotavirus requires pretreatment of the virus ment (encoding one protein). With this approach, the new
with trypsin to generate the ISVP for infection to occur but activity is attributable to the genomic segment from the
is not used for diagnostic purposes.  other virus strain.

TREATMENT, PREVENTION, AND CONTROL Mice, and presumably humans, mount protective
Rotaviruses are acquired very early in life. Their ubiqui- humoral and cellular immune responses to outer capsid
tous nature makes it difficult to limit the spread of the virus proteins. Although orthoreoviruses are normally lytic, they
and infection. Hospitalized patients with disease must be can also establish persistent infection in cell culture. 
isolated to limit spread of the infection to other susceptible
patients. EPIDEMIOLOGY
The virus is primarily spread by the fecal-oral route and
No specific antiviral therapy is available for a rotavi- potentially in aerosols. As previously mentioned, the
rus infection. The morbidity and mortality associated orthoreoviruses have been found worldwide. Most people
with rotavirus diarrhea result from dehydration and are infected during childhood. 
electrolyte imbalance. Similar to the therapy for cholera,
rehydration therapy is necessary to replace fluids so that CLINICAL SYNDROMES
blood volume and electrolyte and acid–base imbalances Orthoreoviruses infect people of all ages; linking specific
are corrected. diseases to these agents has been difficult. Most infections
are asymptomatic or so mild they go undetected. These
Development of a safe rotavirus vaccine was a high pri- viruses have been linked to common coldlike, mild upper
ority for protecting children, especially those in underde- respiratory tract illness (low-grade fever, rhinorrhea, and
veloped countries, from potentially fatal disease. Animal pharyngitis), gastrointestinal tract disease, and biliary
rotaviruses, such as the rhesus monkey rotavirus and the atresia. 
Nebraska calf diarrhea virus, share antigenic determi-
nants with human rotaviruses and do not cause disease LABORATORY DIAGNOSIS
in humans. A human–rhesus monkey reassortant vaccine Human orthoreovirus infection can be detected through
(RotaShield) was recalled in 1999 because of the incidence assay of the viral antigen or genomic RNA or virus isola-
of intussusception (misfolding of the bowel possibly result- tion from throat, nasopharyngeal, and stool specimens, or
ing from inflammatory reactions) in a small number of serologic assays for virus-specific antibody. 
infants, more recently shown to be similar to levels in the
unvaccinated. Two new safer rotavirus hybrid and live vac- TREATMENT, PREVENTION, AND CONTROL
cines have since been developed and are approved by the Orthoreovirus disease is mild and self-limited. For this rea-
U.S. Food and Drug Administration in the United States and son, treatment has not been necessary, and prevention and
elsewhere. RotaTeq consists of five reassortant bovine rota- control measures have not been developed. 
viruses containing the VP4 or VP7 of five different human
rotaviruses. The Rotarix vaccine is a single-strain attenu-
ated human rotavirus. The vaccines are administered
orally as young as possible, at 2, 4, and 6 months of age.

51  •  Reoviruses 513

Coltiviruses and Orbiviruses British Alberta
Columbia
The coltiviruses and orbiviruses infect vertebrates and
invertebrates. The coltiviruses cause Colorado tick fever and WA MT SD
related human disease. The orbiviruses mainly cause disease OR ID WY
in animals, including blue tongue disease of sheep, African
horse sickness, and epizootic hemorrhagic disease of deer. NV UT CO
CA
Colorado tick fever, an acute disease characterized
by fever, headache, and severe myalgia, was originally NM
described in the 19th century and is now believed to be one
of the most common tick-borne viral diseases in the United Fig. 51.6  Geographic distribution of Colorado tick fever.
States. Although hundreds of infections occur annually,
the exact number is not known, because Colorado tick fever Phase I Prolonged viremia
is not a reportable disease. Incubation Prolonged weakness

The structure and physiology of the coltiviruses and orbi- Phase II
viruses are similar to those of the other Reoviridae, with the
following major exceptions: 0 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
1. The outer capsid of the orbiviruses has no discernible Days

capsomeric structure, even though the inner capsid is Fig. 51.7  Time course of Colorado tick fever.
icosahedral.
2 . The virus causes viremia, infects erythrocyte precur- symptomatic infections start with the sudden onset of fever,
sors, and remains in the mature red blood cells, pro- chills, headache, photophobia, myalgia, arthralgia, and
tected from the immune response. lethargy (Fig. 51.7). Characteristics of the infection include
3. The Orbivirus life cycle includes vertebrates and inverte- a biphasic fever, conjunctivitis, and possibly lymphade-
brates (insects). nopathy, hepatosplenomegaly, and a maculopapular or
4 . Colorado tick fever viruses have 12 ds-RNA genomic petechial rash. A leukopenia involving both neutrophils
segments, and orbiviruses have 10. and lymphocytes is an important hallmark of the disease.
Children occasionally have a more severe hemorrhagic dis-
PATHOGENESIS ease. Colorado tick fever must be differentiated from Rocky
Colorado tick fever virus infects erythroid precursor cells Mountain spotted fever, which is a tick-borne rickettsial
without severely damaging them. The virus remains within infection characterized by a rash, because the latter disease
the cells even after they mature into red blood cells; this requires antibiotic treatment. 
factor protects the virus from clearance. The resulting vire-
mia can persist for weeks or months even after cessation of LABORATORY DIAGNOSIS
symptoms. Both of these factors promote transmission of A diagnosis of Colorado tick fever can be established
the virus to the tick vector. through direct detection of viral antigens, genome, virus
isolation, or serologic tests. Viral antigen can be detected
Serious hemorrhagic disease can result from infection of vas- on the surfaces of erythrocytes in a blood smear through
cular endothelial and vascular smooth muscle cells and peri- the use of immunofluorescence, and viral genomes can be
cytes, weakening capillary structure. The weakness leads to detected with RT-PCR. Laboratory tests may be available
leakage, hemorrhage, and potentially hypotension and shock. through state public health departments or the Centers for
Neuronal infection can lead to meningitis and encephalitis.  Disease Control and Prevention. Serology can be performed
for epidemiologic purposes. 
EPIDEMIOLOGY
Colorado tick fever occurs in western and northwestern TREATMENT, PREVENTION, AND CONTROL
areas of the United States and western Canada at elevations No specific treatment is available for Colorado tick fever. The
of 4000 to 10,000 feet, which is the habitat of the wood tick disease is generally self-limited, indicating that supportive
Dermacentor andersoni (Fig. 51.6). Ticks acquire the virus by care is sufficient. The viremia is long lasting, implying that
feeding on a viremic host and subsequently transmit the
virus in saliva when feeding on a new host. Natural hosts
of this virus include many mammals, including squirrels,
chipmunks, rabbits, and deer. Human disease is observed
during the spring, summer, and autumn, seasons when
humans are more likely to invade the habitat of the tick. 

CLINICAL SYNDROMES
Colorado tick fever virus generally causes mild or subclini-
cal infection. The symptoms of the acute disease resemble
those of dengue fever. After a 3- to 6-day incubation period,

514 SECTION 5  •  Virology

infected patients should not donate blood soon after recov- Knipe, D.M., Howley, P.M., 2013. Fields Virology, sixth ed. Lippincott Wil-
ery. Prevention consists of (1) avoiding tick-infested areas, liams & Wilkins, Philadelphia.
(2) using protective clothing and tick repellents, and (3)
removing ticks before they bite. Unlike tick-borne rickettsial Nibert, M.L., Furlong, D.B., Fields, B.N., 1991. Mechanisms of viral patho-
disease, in which prolonged feeding is required for the bac- genesis: distinct forms of reovirus and their roles during replication in
teria to be transmitted, the coltivirus from the tick’s saliva cells and host. J. Clin. Invest. 88, 727–734.
can enter the bloodstream rapidly and is sufficient to initiate
disease. Ramig, R.F., 1994. Rotaviruses. Current Topics in Microbiology and
Immunology, vol. 185. Springer-Verlag, Berlin.
  For a case study and questions see Student­Consult.com
Ramig, R.F., 2007. Systemic rotavirus infection. Expert. Rev. Anti. Infect.
Bibliography Ther. 5, 591–612.

Bellamy, A.R., Both, G.W., 1990. Molecular biology of rotaviruses. Adv. Richman, D.D., Whitley, R.J., Hayden, F.G., 2017. Clinical Virology,
Virol. 38:1–44. fourth ed. American Society for Microbiology Press, Washington, DC.
Blacklow, N.R., Greenberg, H.B., 1991. Viral gastroenteritis. N. Engl. J.
Roy, P., 2006. Reoviruses: Entry, Assembly and Morphogenesis. Current
Med. 325, 252–264. Topics in Microbiology and Immunology, vol. 309. Springer-Verlag,
Burke, R.M., et  al, 2018. Three rotavirus outbreaks in the postvaccine Heidelberg, Germany.

era–California, 2017. MMWR 67(16). Sharpe, A.H., Fields, B.N., 1985. Pathogenesis of viral infections: basic
Burrell, C., Howard, C., Murphy, F., 2016. Fenner and White’s Medical concepts derived from the reovirus model. N. Engl. J. Med. 312, 486–
497.
Virology, fifth ed. Academic, New York.
Christensen, M.L., 1989. Human viral gastroenteritis. Clin. Microbiol. Strauss, J.M., Strauss, E.G., 2007. Viruses and Human Disease, second ed,.
Academic, San Diego.
Rev. 2, 51–89.
Cohen, J., Powderly, W.G., 2004. Infectious Diseases, second ed. Mosby, Tyler, K.L., Oldstone, M.B.A., 1998. Reoviruses. Curr Top Microbiol Cur-
rent Topics in Microbiology and Immunology, vol. 233. Springer-Ver-
St Louis. lag, Berlin.
Flint, S.J., Racaniello, V.R., et al., 2015. Principles of Virology, fourth ed.
Websites
American Society for Microbiology Press, Washington, DC. Centers for Disease Control and Prevention, Rotavirus. www.cdc.gov/rota
Gershon, A.A., Hotez, P.J., Katz, S.L., 2004. Krugman’s Infectious Diseases
virus/. Accessed August 12, 2018.
of Children, eleventh ed. Mosby, St Louis. Centers for Disease Control and Prevention, Rotavirus Vaccines. https://
Greenberg, H.B., Estes, M.K., 2009. Rotaviruses: from pathogenesis to vac-
www.cdc.gov/rotavirus/vaccination.html. Accessed August 12, 2018.
cination. Gastroenterology 136, 1939–1951. 2017 Centers for Disease Control and Prevention, 2018. Three rotavirus

out­breaks in the postvaccine era—California, 2017. MMWR 67 (16).
Nguyen, D.D., Henin, S.S., King, B.R., 2018. Rotavirus. http://emedicine

.medscape.com/article/803885-overview. Accessed August 12, 2018.
Stevenson, A., Chandranesan, J., 2017. Reoviruses. http://emedicine.med

scape.com/article/227348-overview. Accessed August 8, 2018.

Case Study and Questions 4 . How can the disease be prevented?
5 . Why was this baby at such high risk for mortality?
A 10-month-old Pakistani infant has watery diarrhea, 6. Why is it important to immunize with the rotavirus vac-
vomiting, and fever for 4 days. The baby becomes very
dehydrated and dies. cines so early in life and with a live attenuated oral vac-
1 . How could a diagnosis of rotavirus be confirmed? cine?
2. How does this agent cause diarrhea?
3 . What is the treatment?

514.e1

52 Togaviruses and

Flaviviruses

A 5-year-old Indonesian girl died of hemorrhagic 3 . What types of immune responses are protective? Poten-
shock. The presence of dengue virus serotype 3 in tially harmful?
her blood was confirmed by reverse transcriptase-
polymerase chain reaction (RT-PCR). 4 . Where is dengue prevalent? Why?
1 . How was the child infected with dengue virus?
2 . What are the diseases caused by dengue virus?  Answers to these questions are available on Student
Consult.com.

Summaries Clinically Significant Organisms

TOGAVIRUSES ᑏᑏ Rubella: aerosol spread, only infects ᑏᑏ Virus spreads in blood to target tissues:
humans, unvaccinated individuals at for encephalitis viruses neurons and
Trigger Words risk, fetus at high risk brain; for hemorrhagic viruses vascula-
ture, liver, organs
Arboviruses: mosquito, encephalitis Diagnosis
Rubella: German measles, congenital ᑏᑏ Prodrome of flulike symptoms caused by
ᑏᑏ RT-PCR, ELISA interferon and cytokine response
disease, rash, vaccine
Treatment, Prevention, and Control ᑏᑏ Arboviruses
Biology, Virulence, and Disease ᑏᑏ Encephalitis viruses: St. Louis, West Nile,
ᑏᑏ Arboviruses: mosquito control
ᑏᑏ Small size, envelope surrounds icosahe- ᑏᑏ Live attenuated rubella vaccine at 1 year Japanese encephalitis viruses
dral nucleocapsid, (+) RNA genome ᑏᑏ Hemorrhagic disease:
of age in MMR; booster at 4 to 6 years
ᑏᑏ Encodes RNA-dependent RNA poly- Yellow fever: jaundice, black vomit
merase, replicates in cytoplasm FLAVIVIRUSES Dengue: hemorrhagic fever, breakbone

ᑏᑏ Early and late mRNA and proteins Trigger Words fever, dengue shock syndrome
produced
Arboviruses: mosquito, encephalitis, hem- Epidemiology
ᑏᑏ Virus spreads in blood to target tissues, orrhagic diseases
including neurons and brain ᑏᑏ Endemic to habitat of mosquito
Hepatitis C virus: see Chapter 55 ᑏᑏ Arboviruses: zoonosis, reservoir in birds,
ᑏᑏ Antibody can block viremia and disease
ᑏᑏ Prodrome of flulike symptoms caused by Biology, Virulence, and Disease vectors are Aedes or Culex mosquitoes

interferon and cytokine response ᑏᑏ Small size, envelope surrounds icosahe- Diagnosis
ᑏᑏ Arboviruses: equine encephalitis viruses dral nucleocapsid, (+) RNA genome
ᑏᑏ RT-PCR, ELISA
(WEE, EEE, VEE) ᑏᑏ Encodes RNA-dependent RNA poly-
ᑏᑏ Rubella: benign childhood rash, swollen merase, replicates in cytoplasm Treatment, Prevention, and Control

glands. Adult complications include ᑏᑏ Neutralizing antibody can block disease ᑏᑏ Arboviruses: mosquito control
arthritis, encephalitis. Congenital infec- ᑏᑏ Nonneutralizing antibody promotes ᑏᑏ Yellow fever virus: attenuated live
tion: teratogenic, cataracts, deafness,
microcephaly, etc. dengue virus infection v­ accine
ᑏᑏ Cross-reactive antibodies produced
Epidemiology
against different flaviviruses
ᑏᑏ Arboviruses: zoonosis, reservoir in birds,
vectors are Aedes and Culex mosquitoes

EEE, Eastern equine encephalitis; ELISA, enzyme-linked immunosorbent assay; MMR, measles-mumps- rubella; RT-PCR, reverse transcriptase-polymerase chain
reaction; VEE, Venezuelan equine encephalitis; WEE, western equine encephalitis.

The members of the Togaviridae and Flaviviridae fami- it is discussed separately because its disease manifestation
lies are enveloped, positive-sense, single-stranded ribonu- (German measles) and its means of spread differs from
cleic acid (RNA) viruses (Box 52.1). The Alphavirus genus those of the alphaviruses. The Flaviviridae include the fla-
of togaviruses and Flavivirus differ in size, morphology, viviruses, pestiviruses, and hepaciviruses (hepatitis C and G
gene sequence, and replication but are discussed together viruses). Hepatitis C and G are discussed in Chapter 55.
because of similarities in the diseases they cause and in their
epidemiology. Most are transmitted by arthropods and are Alphaviruses and Flaviviruses
therefore arboviruses (arthropod-borne viruses).
Alphaviruses and flaviviruses are classified as arboviruses
The Togaviridae (togaviruses) that cause human disease because they are spread by arthropod vectors. These viruses
are in the Alphavirus and Rubivirus genera (Table 52.1).
Rubella virus is the only member of the Rubivirus group; 515

516 SECTION 5  •  Virology

BOX 52.1  Unique Features of Togaviruses vesicle to deliver the capsid and genome into the cytoplasm.
and Flaviviruses Once released into the cytoplasm, the alphavirus genomes
bind to ribosomes as mRNA. The alphavirus genome is
Viruses have enveloped, single-stranded, positive-sense RNA. translated in early and late phases. The initial two-thirds
Togavirus replication includes early (nonstructural) and late (struc- of the alphavirus RNA is translated into a polyprotein that
includes proteases that subsequently cleave the polyprotein
tural) protein synthesis. into four nonstructural early proteins (NSPs 1 through 4).
Togaviruses replicate in the cytoplasm and bud at plasma mem- These early proteins are components of the RNA-dependent
RNA polymerase. As for all positive strand RNA viruses, the
branes. enzymes for replication of the genome assemble on a mem-
Flaviviruses replicate in the cytoplasm and bud at intracellular brane scaffold in a vesicle. First, a full-length 42S negative-
sense RNA is synthesized as a template for replication of the
membranes. genome, and then more 42S positive-sense mRNA is pro-
duced. In addition, a 26S late mRNA, corresponding to one-
TABLE 52.1  Togaviruses and Flaviviruses third of the genome, is transcribed from the template. The
26S RNA encodes the capsid (C) and envelope (E1 through
Virus Group Human Pathogens E3) proteins. Late in the replication cycle, viral mRNA can
TOGAVIRUSES account for as much as 90% of the mRNA in the infected
 Alphavirus Arboviruses cell. The abundance of late mRNAs allows production of a
 Rubivirus Rubella virus large amount of the structural proteins required for packag-
 Arterivirus None ing the virus.
FLAVIVIRUSES Arboviruses
 Hepaciviridae Hepatitis C virus The structural proteins are produced by protease cleav-
 Pestivirus None age of the late polyprotein that was produced from the 26S
mRNA. The C protein is translated first and is cleaved from
have a very broad host range, including vertebrates (e.g., the polyprotein. A signal sequence is then made that associ-
mammals, birds, amphibians, reptiles) and invertebrates ates the nascent polypeptide with the endoplasmic reticu-
(e.g., mosquitoes, ticks). Diseases spread by animals or lum. Thereafter, envelope glycoproteins are translated,
with an animal reservoir are called zoonoses. Examples of glycosylated, and cleaved from the remaining portion of
pathogenic alphaviruses and flaviviruses are listed in Table the polyprotein to produce the E1, E2, and E3 glycoprotein
52.2. spikes. The E3 is released from most alphavirus glycopro-
tein spikes. The glycoproteins are processed by the normal
STRUCTURE AND REPLICATION OF cellular machinery in the endoplasmic reticulum and Golgi
ALPHAVIRUSES apparatus and are acetylated and acylated with long-chain
The alphaviruses have an icosahedral capsid and a fatty acids. Alphavirus glycoproteins are then transferred
positive-sense, single-strand RNA genome that resembles efficiently to the plasma membrane.
messenger RNA (mRNA). They are slightly larger than
picornaviruses (45 to 75 nm in diameter) and are sur- The C proteins associate with the genomic RNA soon
rounded by an envelope (Latin toga, “cloak”). The togavi- after their synthesis and form an icosahedral capsid. Once
rus genome encodes early and late proteins. this step is completed, the capsid associates with portions
of the membrane expressing the viral glycoproteins. The
Alphaviruses have two or three glycoproteins that asso- alphavirus capsid has binding sites for the C-terminus of
ciate to form a single spike. The carboxy (COOH) terminus the glycoprotein spike, which pulls the envelope tightly
of the glycoproteins is anchored in the capsid, forcing the around itself in a manner like shrink-wrap (see Figs. 52.1
envelope to wrap tightly (“shrink-wrap”) and take on the and 52.2). Alphaviruses are released on budding from the
shape of the capsid (Fig. 52.1). The capsid proteins of all the plasma membrane of human cells. They are cytolytic for
alphaviruses are similar in structure and are antigenically human but not insect cells.
cross-reactive. The viruses can be grouped (complexes) and
distinguished by different antigenic determinants on their Of interest, the western equine encephalitis virus
envelope glycoproteins. (WEEV) was created by recombination of two alphavi-
ruses, the eastern equine encephalitis virus (EEEV) and
The alphaviruses attach to specific receptors expressed on the Sindbis virus. The beginning of the WEEV genome is
many different cell types from many different species (Fig. almost identical to EEEV, with similar glycoproteins and
52.2). The host range for these viruses includes vertebrates virulence genes, whereas the end of the genome resembles
(e.g., humans, monkeys, horses, birds, reptiles, amphibians) Sindbis. 
and invertebrates (e.g., mosquitoes, ticks). However, the
individual viruses have different tissue tropisms, account- STRUCTURE AND REPLICATION OF
ing somewhat for the different disease presentations. FLAVIVIRUSES
The flaviviruses also have a positive-strand RNA genome,
The virus enters the cell by means of receptor-mediated an icosahedral capsid, and an envelope but are slightly
endocytosis (see Fig. 52.2). The viral envelope then fuses smaller than an alphavirus (40 to 65 nm in diameter).
with the membrane of the endosome on acidification of the The E viral glycoprotein folds over, pairs up with another
E glycoprotein, and lies flat across the surface of the virion
to form an outer protein layer (see Fig. 52.1). Most of the

TABLE 52.2 Arboviruses

Virus Vector Host Distribution Disease
ALPHAVIRUSES
Sindbisa Aedes and other mosquitoes Birds Africa, Australia, India Subclinical
Semliki Foresta Aedes and other mosquitoes Birds Subclinical
Aedes, Culex Rodents, horses East and West Africa Mild systemic; severe
Venezuelan equine encephalitis
Birds North, South, and Central encephalitis
Eastern equine encephalitis Aedes, Culiseta America Mild systemic; encephalitis
Birds
Western equine encephalitis Culex, Culiseta Humans, monkeys North and South America, Mild systemic; encephalitis
Aedes Caribbean Fever, arthralgia, arthritis
Chikungunya Humans, monkeys
FLAVIVIRUSES Aedes North and South America
Denguea Humans, monkeys
Humans, monkeys, Africa, Asia

Yellow fevera Aedes rodents Worldwide, especially Mild systemic; breakbone
Zika Aedes Pigs, birds tropics fever, dengue hemor-
Birds rhagic fever, and dengue
Japanese encephalitis Culex Africa, South America shock syndrome
West Nile encephalitis Culex Birds Worldwide, especially
Birds Hepatitis, hemorrhagic fever
St. Louis encephalitis Culex tropics
Russian spring-summer lxodes and Dermacentor ticks Small mammals Asia Systemic, rash, arthralgia,
Africa, Europe, Central Asia, congenital disease
encephalitis lxodes ticks
Powassan encephalitis North America Encephalitis
aPrototypical viruses. North America
Russia Fever, encephalitis, hepatitis

Encephalitis

Encephalitis

North America Encephalitis

A E1, E2
glycoproteins
Envelope
E1, E2
glycoproteins
(+) RNA

B Togavirus C Flavivirus

Fig. 52.1  Alphavirus morphology. (A) Morphology of the alphavirus virion obtained from cryoelectron microscopy and image processing of the micro-
graphs to show that the envelope is held tightly and conforms to the icosahedral shape and symmetry of the capsid. (B) Cross section of alpha-togavirus.
The envelope is tightly associated with the capsid. (C) Cross section of flavivirus. The envelope protein surrounds the membrane envelope, which
encloses an icosahedral nucleocapsid. RNA, Ribonucleic acid. (A, From Fuller, S.D., 1987. The T = 4 envelope of Sindbis virus is organized by interactions with
a complementary T = 3 capsid. Cell 48, 923–934.)

518 SECTION 5  •  Virology

Nucleus Togavirus genome (Sindbis virus) 42S genomic RNA 3؅
5؅
12 PolyA
CAP
RNA genome NSP-1 NSP-2 NSP-3 NSP-4 C Pe2 6K E1
26S late transcript
CAP

5′ Genome 5–
+
3 + 7
– 6 9 E1 E3 E2
5′ E2 Structural protein genes
26s mRNA E3 Nonstructural protein genes
Polyprotein N
p230 AAA
p270
C Flavivirus genome (yellow fever virus)

48

CAP NS-1 NS2a NS3 NS4a NS4b NS5
C PrM E

NS2b

Fig. 52.2  Replication of a togavirus. 1, Togaviruses bind to cell recep- Pr M Nonstructural protein genes
tors and are internalized in a coated vesicle. 2, On acidification of the
endosome, the viral envelope fuses with the endosomal membrane Structural protein
to release the nucleocapsid into the cytoplasm. 3, Ribosomes bind to genes
the positive-sense ribonucleic acid (RNA) genome, and the p230 or
p270 (full-length) early polyproteins are made. 4, The polyproteins Fig. 52.3  Comparison of the togavirus (alphavirus) and flavivirus
are cleaved to produce nonstructural proteins 1 to 4 (NSP1 to NSP4), genomes. Alphavirus: The enzymatic activities are translated from the 5′
which include a polymerase to transcribe the genome into a negative- end of the input genome, promoting their early rapid translation. The
sense RNA template. 5, The replication enzymes assemble onto cellular structural proteins are translated later from a smaller messenger ribo-
membrane scaffolds in vesicles, and the template is used to produce nucleic acid (mRNA) transcribed from the genomic template. Flavivirus:
a full-length 42S positive-sense mRNA genome and a late 26S mRNA The genes for the structural proteins of the flaviviruses are at the 5′ end
for the structural proteins. 6, The capsid (C) protein is translated first of the genome/mRNA, and only one species of polyprotein is made,
and cleaved. A signal peptide is exposed, the peptide associates with which represents the entire genome. PolyA, Polyadenylate.
the endoplasmic reticulum 7, in which the E glycoproteins are synthe-
sized and glycosylated. They are transferred to the Golgi apparatus polyprotein associates with the endoplasmic reticulum
and then the plasma membrane. 8, The capsid proteins assemble on membrane and then is cleaved into its components. Unlike
the 42S genomic RNA and then associate with regions of cytoplasmic the togaviruses, the flaviviruses acquire their envelope by
and plasma membranes containing the E1, E2, and E3 spike proteins. 9, budding into the endoplasmic reticulum rather than at the
Budding from the plasma membrane releases the virus. AAA, Polyad- cell surface. The virus is then released by exocytosis or cell
enylate; mRNA, messenger ribonucleic acid. lysis mechanisms. This route is less efficient, and the virus
may remain cell associated. 
flaviviruses are antigenically related, and antibodies to one
virus may recognize and neutralize another virus. ARBOVIRUS PATHOGENESIS AND IMMUNITY
Because the arboviruses are acquired from the bite of an
Attachment and penetration of the flaviviruses occur arthropod such as a mosquito, knowledge of the course of
in the same way as described for the alphaviruses. Anti- infection in both the vertebrate host and the invertebrate
body can enhance infectivity and promote viral uptake vector is important for an understanding of the diseases.
into macrophages, monocytes, and other cells that have Infections of invertebrates are usually persistent, with con-
Fc receptors when the virus is coated with antibody. The tinued virus production.
major differences between alphaviruses and flaviviruses
are in the organization of their genomes and their mecha- The death of an infected cell results from a combination
nisms of protein synthesis. The entire flavivirus genome of virus-induced insults. Increased permeability of the tar-
is translated into a single polyprotein in a manner more get cell membrane and changes in ion concentrations can
similar to the process for picornaviruses than for alphavi- alter enzyme activities and favor the translation of viral
ruses (Fig. 52.3). As a result, there is no temporal distinc- mRNA over cellular mRNA. The large amount of viral
tion in the translation of the different viral proteins. The RNA produced on the replication and transcription of the
polyprotein produced from the yellow fever genome con- genome blocks cellular mRNA from binding to ribosomes.
tains 10 proteins, including a protease and components of The displacement of cellular mRNA from the protein syn-
the RNA-dependent RNA polymerase, plus the capsid and thesis machinery prevents rebuilding and maintenance
envelope proteins. of the cell and is a major cause of the death of the virus-
infected cell.
Unlike in the alphavirus genome, the structural genes are
at the 5′-end of the flavivirus genome. As a result, the por- Female mosquitoes acquire the alphaviruses and flavivi-
tions of the polyprotein containing the structural (not the ruses by taking a blood meal from a viremic vertebrate
catalytic) proteins are synthesized first and with the great- host. A sufficient viremia must be maintained in the vertebrate
est efficiency and the polymerase (NS5) is last. This arrange- host to allow acquisition of the virus by the mosquito. The virus
ment allows production of more structural proteins, but it then infects the epithelial cells of the midgut of the mos-
decreases the efficiency of nonstructural protein synthesis quito, spreads through the basal lamina of the midgut to
and the initiation of viral replication. The entire flavivirus the circulation, and infects the salivary glands. The virus

52  •  Togaviruses and Flaviviruses 519

BOX 52.2  Disease Mechanisms of Togaviruses and Flaviviruses

Viruses are cytolytic, except for rubella and hepatitis C.
Viruses establish viremia and systemic infection.
Viruses are good inducers of interferon and cytokines, which can account for the flulike symptoms during prodrome.
Viruses, except rubella and hepatitis C, are arboviruses.
Flaviviruses can infect cells of the monocyte-macrophage lineage.
Nonneutralizing antibody can enhance flavivirus infection via Fc receptors on cells.

Flulike/Systemica Encephalitis Hepatitis Hemorrhage Shock

Dengue + — + + +
Yellow fever + — + + +
Zikab + — — — —
St. Louis encephalitis + + — — —
West Nile encephalitis + + — — —
Chikungunya + — — — —
Eastern equine encephalitis + + — — —
Japanese encephalitis + + — — —

aSystemic symptoms may include arthralgia
bCan cause microcephaly in fetus.

sets up a persistent infection and replicates to high titers in endothelial cells exacerbated by extensive cytokine produc-
these cells. The salivary glands can then release virus into tion (cytokine storm), which induces vascular leakage. 
the saliva. Not all arthropod species can generate virus in
their saliva. For example, the normal vector for WEEV is the IMMUNE RESPONSE
Culex tarsalis mosquito, but certain strains of virus are lim- Replication of the alphaviruses and flaviviruses produces
ited to the midgut of this mosquito, cannot infect its salivary a double-stranded RNA replicative intermediate that is a
glands, and therefore cannot be transmitted to humans. good inducer of interferon (IFN)-α and IFN-β. The inter-
feron limits replication of the virus and is also released into
On biting a host, the female mosquito regurgitates virus- the bloodstream to stimulate innate and immune responses.
containing saliva into the skin and the victim’s blood- Interferon and other cytokines are produced after infection
stream. The primary target cells of the flaviviruses are of of plasmacytoid dendritic and other cells in blood, causing
the monocyte-macrophage lineage, including dendritic rapid onset of the flulike symptoms characteristic of mild
cells. Although these cells are found throughout the body systemic disease.
and may have different characteristics, they express Fc
receptors for antibody and release cytokines on challenge. Circulating immunoglobulin (Ig)M is produced within 6
Flavivirus infection is enhanced 200- to 1000-fold by non- days of infection, followed by production of IgG. Antibody
neutralizing antiviral antibody that promotes binding of the to the viral attachment protein blocks viremic spread of the
virus to the Fc receptors and its uptake into the cell. The virus and subsequent infection of other tissues. Through
virus also infects the endothelial cells of capillaries. recognition of the type-common antigens expressed on
all viruses in the family, immunity to one flavivirus may
These viruses are associated with mild systemic disease, provide some protection against infection with other flavi-
encephalitis, arthrogenic disease, or hemorrhagic viruses. Cell-mediated immunity is also important in con-
disease (Box 52.2). The ultimate nature of alphavirus trolling the primary infection.
and flavivirus disease is determined by (1) the specific tis-
sue tropisms of the individual virus type, (2) the concentra- Immunity to these viruses is a double-edged sword. The
tion of infecting virus, and (3) individual responses to the interferon and cytokine responses cause the prodrome and
infection. systemic symptoms, including the arthritides. Inflammation
and cytolysis resulting from complement and cell-mediated
The initial viremia produces systemic symptoms such as immune responses can destroy tissues and significantly
fever, chills, headaches, backaches, and other flulike symp- contributes to the pathogenesis of encephalitis. Hypersen-
toms within 7 days of infection. Most of these symptoms sitivity reactions to cell-associated antibody or initiated by
can be attributed to the effects of the interferon and other formation of immune complexes with virions and viral anti-
cytokines produced in response to the viremia and infection gens can activate complement and disrupt vascular cells to
of host cells. Most viral infections do not progress beyond cause the hemorrhagic symptoms. An antibody to another
the mild systemic disease associated with viremia. A sec- flavivirus that does not neutralize the virus can enhance the
ondary viremia can produce sufficient virus to infect target uptake of flaviviruses into macrophages and other cells that
organs (e.g., brain, liver, skin, vasculature), depending on express Fc receptors. Immune responses to a related strain
the tissue tropism of the virus (Fig. 52.4). The virus gains of dengue virus that do not prevent infection can exacer-
access to the brain by infecting the endothelial cells lining bate immunopathogenesis, leading to dengue hemorrhagic
the small vessels of the brain or the choroid plexus. Hemor- fever (DHF) or dengue shock syndrome (DSS). 
rhagic disease and shock, as for dengue virus, results from
viral and immune-induced cytolysis of infected vascular

520 SECTION 5  •  Virology

2-3 Mild or asymptomatic BOX 52.3  Epidemiology of Alphavirus and
days presentation Flavivirus Infection

Prodrome Disease/Viral Factors
Viremia
Enveloped virus must stay wet and can be inactivated by drying,
3-7 Mild systemic soap, and detergents.
days disease, fever,
Virus can infect mammals, birds, reptiles, and insects.
aches, chills Macrophage Liver Spleen, Asymptomatic or nonspecific (flulike fever or chills), encephalitis,
Vascular lymph nodes
endothelium hemorrhagic fever, or arthralgia. 

Viremia Transmission

Severe or Specific arthropods characteristic of each virus (zoonosis: arbovi-
life-threatening rus). 
presentation Encephalitis
Who Is at Risk?
Hemorrhagic
fever People who enter ecologic niche of arthropods infected by arbo-
viruses. 
Yellow fever,
hepatitis Geography/Season

DHF/DSS Endemic regions for each arbovirus are determined by habitat of
Severe systemic disease mosquito or other vector.

Fig. 52.4  Disease syndromes of the alphaviruses and flaviviruses. Aedes mosquito, which carries dengue and yellow fever, is found
Primary viremia may be associated with mild systemic disease. Most in urban areas and in pools of water.
infections are limited to this. If sufficient virus is produced during the
secondary viremia to reach critical target tissues, then severe systemic Culex mosquito, which carries St. Louis encephalitis and West Nile
disease or encephalitis may result. If antibody is present (X), viremia encephalitis viruses, is found in forest and urban areas.
is blocked. For dengue virus, rechallenge with another strain can
result in severe dengue hemorrhagic fever (DHF), which can cause Disease is more common in summer. 
dengue shock syndrome (DSS) because of the loss of fluids from the
­vasculature. Modes of Control

EPIDEMIOLOGY Mosquito breeding sites and mosquitoes should be eliminated.
Alphaviruses and most flaviviruses are prototypical arbovi- Live attenuated yellow fever virus and inactivated Japanese
ruses (Box 52.3). To be an arbovirus, the virus must be able
to (1) infect both vertebrates and invertebrates, (2) initiate a encephalitis virus vaccines.
sufficient viremia in a vertebrate host for a sufficient time to
allow acquisition of the virus by the invertebrate vector, and and geographic distribution of representative alphaviruses
(3) initiate a persistent productive infection of the salivary and flaviviruses are listed in Table 52.2.
gland of the invertebrate to provide virus for the infection
of other host animals. Humans are usually “dead-end” These viruses are usually restricted to a specific arthro-
hosts in that they cannot spread the virus back to the vec- pod vector, its vertebrate host, and their ecologic niche. The
tor because they do not maintain a persistent viremia. If the most common vector is the mosquito, but ticks and sandflies
virus is not in the blood, the mosquito cannot acquire it. A full spread some arboviruses. Even in a tropical region overrun
cycle of infection occurs when the virus is transmitted by with mosquitoes, spread of these viruses is still restricted to
the arthropod vector and amplified in a susceptible, immu- a specific genus of mosquitoes. Not all arthropods can act as
nologically naive host (reservoir), allowing reinfection of good vectors for each virus. For example, C. quinquefascia-
other arthropods (Fig. 52.5). The vectors, natural hosts, tus is resistant to infection by WEEV (alphavirus) but is an
excellent vector for St. Louis encephalitis virus (flavivirus).

Birds and small mammals are the usual reservoir hosts for
the alphaviruses and flaviviruses, but reptiles and amphib-
ians also can act as hosts. A large population of viremic ani-
mals can develop in these species to continue the infection
cycle of the virus. For example, West Nile encephalitis virus
(WNV) was first noted in 1999 as an outbreak in New York
by the unusual deaths of captive birds at the Bronx Zoo.
RT-PCR analysis identified the virus as WNV. The virus is
transmitted by C. pipiens mosquitoes, and crows, blue jays,
and other wild birds are the reservoir. The virus spread
throughout the United States, and by 2006, the virus and
human disease had been noted in almost every state. WNV
establishes a sufficient viremia in humans to be a risk factor
for transmission through blood transfusions. Documenta-
tion of two such cases has led to screening blood donors for
WNV and rejecting donors who have fever and headache
during the week of blood donation.

Arbovirus diseases occur during the summer months
and rainy seasons, when the arthropods breed, and the

52  •  Togaviruses and Flaviviruses 521

Natural host Vector Host or jungle cycle, in which monkeys are the natural host,
WEEV (Culex) and also in an urban cycle, in which humans are the host.
EEEV A. aegypti, a vector for each of these viruses, is a house-
hold mosquito. It breeds in pools of water, open sewers,
VEEV and other accumulations of water in cities. The incidence
of chikungunya has greatly increased since 2000 and is
(Culex, Aedes) prevalent from western Africa across southern Asia to the
Philippines and in South America, the Caribbean Islands,
St. Louis, (Culex) and tropical United States. St. Louis encephalitis and WNV
West Nile are maintained in an urban environment because their vec-
encephalitis tors, Culex mosquitoes, breed in stagnant water, including
Dengue puddles and sewage, and the reservoir group includes com-
Yellow fever mon city birds (e.g., crows).

Jungle (Aedes) Urban In addition to transmission by mosquitos, Zika virus
also can be spread in blood, during unprotected sex, and in
Russian (Ixodes) utero to the fetus. According to the Centers for Disease Con-
spring- trol and Prevention, risk for transmission by these routes
summer remains for at least 3 months after a potential exposure
encephalitis (travel to an endemic region). 

Milk CLINICAL SYNDROMES
More humans are infected with alphaviruses and flavivi-
Fig. 52.5  Patterns of alphavirus and flavivirus transmission. Birds and ruses than show significant characteristic symptoms. The
small mammals are the hosts that maintain and amplify an arbovirus, incidence of arbovirus disease is sporadic. Alphavirus infec-
which is spread by the insect vector during a blood meal. A double tions are usually asymptomatic or cause low-grade disease
arrow indicates a cycle of replication in both host (including man) and such as flulike symptoms (chills, fever, rash, aches) that
vector. “Dead-end” infections with no transmission of the virus back correlate with systemic infection during the initial viremia.
to the vector are indicated by the single arrow. EEEV, Eastern equine EEEV, WEEV, and Venezuelan equine encephalitis virus
encephalitis virus; VEEV, Venezuelan equine encephalitis virus; WEEV, (VEEV) infections can progress to encephalitis in humans.
western equine encephalitis virus. The equine encephalitis viruses are usually more of a prob-
lem to livestock than to humans. An affected human may
arboviruses are cycled among a host reservoir (birds), an experience fever, headache, and decreased consciousness
arthropod (e.g., mosquitoes), and human hosts. This cycle 3 to 10 days after infection. Unlike herpes simplex virus
maintains and increases the amount of virus in the envi- encephalitis, the disease will often resolve without signifi-
ronment. In the winter, the vector is not present to main- cant sequelae, but there is the possibility of paralysis, men-
tain the virus. The virus may either (1) persist in arthropod tal disability, seizures, and death.
larvae or eggs or in reptiles or amphibians that remain in
the locale or (2) migrate with the birds and then return dur- The name chikungunya (Swahili for “that which bends
ing the summer. up”) refers to the crippling arthritis associated with serious
disease caused by infection with these viruses. A typical symp-
When humans travel into the ecologic niche of the mos- tomatic infection presents as a week of fever and joint pain.
quito vector, they risk being infected by the virus. Pools of
standing water, drainage ditches, and trash dumps in cities Most flavivirus infections are relatively benign, but seri-
can also provide breeding grounds for mosquitoes such as ous aseptic meningitis and encephalitic or hemor-
Aedes aegypti, which is the vector for yellow fever, dengue, rhagic disease can occur. The encephalitis viruses include
and chikungunya viruses. An increase in the population St. Louis, West Nile, Japanese, Murray Valley, and Rus-
of these mosquitoes, as has occurred in the United States, sian spring-summer viruses. Symptoms and outcomes are
increases the risk for human infection. Health departments similar to those of the togavirus encephalitides. Approxi-
in many areas monitor birds and mosquitoes caught in mately 20% of individuals infected with WNV will develop
traps for arboviruses and initiate control measures such as West Nile fever, characterized by fever, headache, tiredness,
insecticide spraying when necessary. and body aches, occasionally with a rash on the trunk of
the body and swollen lymph glands usually lasting only a
Urban outbreaks of arbovirus infections occur when the few days (Clinical Case 52.1). Encephalitis, meningitis, or
reservoirs for the virus are humans or urban animals (see meningoencephalitis occurs in approximately 1% of WNV-
Fig. 52.5). Yellow fever, dengue, Zika and chikungunya infected individuals. Individuals older than 50 years and the
viruses are transmitted by Aedes mosquitoes in a sylvatic immunocompromised are at higher risk for serious disease.

The hemorrhagic viruses are dengue and yellow fever
viruses. Dengue virus is a major worldwide problem, with
at least 100 million cases of dengue fever and 300,000
cases of DHF occurring per year. The virus and its vector
are present in central and northern South America, and
cases have occurred in Puerto Rico, Texas, and Florida. The
incidence of the more serious DHF has quadrupled since

522 SECTION 5  •  Virology

Clinical Case 52.1  West Nile Encephalitis Health Organization (WHO) estimates that 50 to 100 mil-
Virus lion infections occur yearly, including 500,000 DHF cases
and 22,000 deaths, mostly among children.
Hirsch and Warner (N Engl J Med 348:2239–2247, 2003)
described the case of a 38-year-old Massachusetts woman Yellow fever infections are characterized by severe sys-
who presented with a progressively worsening headache temic disease, with degeneration of the liver, kidney, and
with photophobia and fever. Because it was August, she heart, as well as hemorrhage. Liver involvement causes the
was on summer vacation and 10 days earlier (−10) had jaundice from which the disease gets its name, but massive
traveled to St. Louis and stayed for 8 days. While there, gastrointestinal hemorrhages (“black vomit”) may also
she walked in the woods and visited the zoo. A day before occur. The mortality rate associated with yellow fever dur-
the onset of these symptoms (−1), she vacationed along ing epidemics is as high as 50%.
the Atlantic shore and noted that she had been bitten by
mosquitos and removed ticks from her dog. Four days later Zika virus infection is usually asymptomatic. Disease
(+4), she was admitted with fever (40° C), chills, rapid resembles mild cases of dengue and chikungunya with
heartbeat, confusion, lightheadedness, and lethargy. Al- fever, rash, headache, muscle and joint pain and conjunc-
though appearing alert, oriented, and only slightly ill, her tivitis. Infection correlates with higher incidence of Guil-
neck was rigid and Kernig sign was present. The signs of lain-Barré syndrome. Despite a lack of symptoms, the virus
meningitis prompted testing of cerebrospinal fluid, which can be transmitted sexually and vertically to the fetus for
contained IgM to WNV and low titers to SLE virus. Patient at least 3 months after infection. Infection of the fetus can
antibody neutralized WNV but not SLE virus infection of cause microcephaly and other congenital abnormalities. 
tissue culture cells, suggesting that the activity to SLE was
caused by cross-reactivity between flaviviruses. Tests for LABORATORY DIAGNOSIS
other organisms were negative. She was treated empirical- Detection and characterization of the alphaviruses and
ly for meningitis and for HSV (acyclovir). Antibacterial and flaviviruses is now performed by RT-PCR testing of viral
anti-HSV treatment for meningitis and encephalitis was mRNA in blood or other samples. Monoclonal antibodies to
necessary until the laboratory results were available. On the individual viruses have become a useful tool for distin-
day 5 post onset, she became more lethargic and had dif- guishing the individual species and strains of viruses. The
ficulty answering questions. MRI indicated subtle changes alphaviruses and flaviviruses can be grown in both verte-
in the brain. On day 6, she could not distinguish her right brate and mosquito cell lines, but most are difficult to iso-
from her left hand, but her headache lessened, and she late. A variety of serologic methods can be used to diagnose
could respond to commands. On day 7, she had a tremor in infections, but the serologic cross-reactivity among viruses
her right arm, but her mental status was improving, and limits distinction of the actual viral species in many cases. 
by day 8, she was alert and lucid. On day 9, a cranial MRI
was normal; on day 10, she was recovered; and on day 11, TREATMENT, PREVENTION, AND CONTROL
she was released from the hospital. The season of the year, No treatments exist for arbovirus diseases, other than sup-
exposure to insects, and travel by this woman were sug- portive care. The easiest means of preventing the spread of any
gestive of several different arboviral encephalitis diseases arbovirus is elimination of its vector and breeding grounds.
in addition to WNV. Viruses in the differential diagnosis After 1900, when Walter Reed and his colleagues discov-
included eastern equine encephalitis, SLE, Powassan virus ered that yellow fever was spread by A. aegypti, the num-
(tick-borne flavivirus), HSV, and WNV. Unlike HSV en- ber of cases was reduced from 1400 to none within 2 years,
cephalitis, flavivirus meningoencephalitis usually resolves purely through control of the mosquito population. Many
with limited sequelae. public health departments monitor bird and mosquito pop-
HSV, Herpes simplex virus; Ig, immunoglobulin; MRI, mag- ulations in a region for arboviruses and periodically spray
to reduce the mosquito population. Avoidance of the breed-
netic resonance imaging; SLE, St. Louis encephalitis; WNV, ing grounds of a mosquito vector is also a good preventive
West Nile virus. measure.

1985. Dengue fever is also known as breakbone fever; A live vaccine against yellow fever virus and killed vac-
the symptoms and signs consist of high fever, headache, cines against EEEV, WEEV, Japanese encephalitis virus, and
rash, hemorrhagic presentations, and back and bone pain Russian spring-summer encephalitis virus are available. A
that last 6 to 7 days. Petechiae (10 or more per square inch) live Japanese encephalitis virus vaccine is used in China.
under the cuff while testing blood pressure (tourniquet test) These vaccines are meant for people working with the virus
is indicative of dengue. On rechallenge with another of the or at risk for contact. A live vaccine against VEEV is avail-
four related strains, dengue can also cause DHF and DSS. able but only for use in domestic animals. Vaccines consist-
Nonneutralizing antibody promotes uptake of the virus ing of all four strains of dengue virus are being developed
into macrophages, which causes memory T cells to become to ensure that immune enhancement of the disease on sub-
activated, release cytokines, and initiate inflammatory sequent challenge does not occur. An interesting approach
reactions. These reactions and the virus result in weaken- to the dengue virus vaccine consists of chimeric viruses
ing and rupture of the vasculature, internal bleeding, and in which the glycoprotein and other genes for each of the
loss of plasma, leading to shock symptoms and internal other dengue virus strains is inserted into either an attenu-
bleeding. Dengue is endemic in at least 100 countries in ated dengue 2 virus or the 17D yellow fever virus.
Asia, the Pacific, the Americas, Africa, and the Caribbean,
accounting for 40% of the world’s population. The World The yellow fever vaccine is prepared from the 17D strain
isolated from a patient in 1927 and grown for long periods

52  •  Togaviruses and Flaviviruses 523

in monkeys, mosquitoes, embryonic tissue culture, and
embryonated eggs. The vaccine is administered intrader-
mally and elicits lifelong immunity to yellow fever and pos-
sibly other cross-reacting flaviviruses. 

Rubella Virus Lymph Liver
nodes
Rubella virus has the same structural properties and mode
of replication as the other togaviruses. However, unlike the Spleen
other togaviruses, rubella is a respiratory virus and does Macrophage
not cause readily detectable cytopathologic effects.
Primary
Rubella is one of the five classic childhood exan- Reticuloendothelial viremia
thems, along with measles, roseola, fifth disease, and
chickenpox. Rubella, meaning “little red” in Latin, was first system
distinguished from measles and other exanthems by Ger- Tissue and
man physicians; thus the common name for the disease, skin
German measles. In 1941, an astute Australian ophthal-
mologist, Norman McAlister Gregg, recognized that mater- Secondary
nal rubella infection was the cause of congenital cataracts. viremia
Maternal rubella infection has since been correlated with
several other severe congenital defects. This finding Placenta,
prompted the development of a unique program to vacci- fetus
nate children to prevent infection of pregnant women and
neonates. Congenital
infection
PATHOGENESIS AND IMMUNITY
Rubella virus is not cytolytic but does interfere with cellular Fig. 52.6  Spread of rubella virus within the host. Rubella enters and
machinery. The replication of rubella prevents (in a process infects the nasopharynx and lung and then spreads to the lymph nodes
known as heterologous interference) the replication of and monocyte-macrophage system. The resulting viremia spreads the
superinfecting picornaviruses. This property allowed the virus to other tissues and the skin. Circulating antibody can block the
first isolations of rubella virus in 1962. transfer of virus at the indicated points (X). In an immunologically defi-
cient pregnant woman, the virus can infect the placenta and spread to
Rubella infects the upper respiratory tract and then the fetus.
spreads to local lymph nodes, which coincides with a period
of lymphadenopathy (Fig. 52.6). This stage is followed by may not be cytolytic, but the normal growth, mitosis, and
establishment of viremia, which spreads the virus through- chromosomal structure of the cells of the fetus can be altered
out the body. Infection of other tissues and the characteristic by the infection. The alterations can lead to improper devel-
mild rash occur. The prodromal period lasts approximately opment of the fetus, small size of the infected baby, and the
2 weeks (Fig. 52.7). The infected person can shed virus in teratogenic effects associated with congenital rubella
respiratory droplets during the prodromal period and for as infection. The nature of the disorder is determined by the
long as 2 weeks after the onset of the rash.  (1) tissue affected and (2) stage of development disrupted.
Since the vaccine era, cytomegalovirus has replaced rubella
IMMUNE RESPONSE as the most common cause of congenital defects.
Antibody is generated after the viremia, and its appearance
correlates with the appearance of the rash. The antibody The virus may persist in tissues such as the lens of the
limits viremic spread, but cell-mediated immunity plays an eye for 3 to 4 years and may be shed up to a year after birth.
important role in resolving the infection. Only one serotype
of rubella exists, and natural infection produces lifelong
protective immunity. Most important, serum antibody in a
pregnant woman prevents spread of the virus to the fetus.
Immune complexes most likely cause the rash and arthralgia
associated with rubella infection. 

CONGENITAL INFECTION
Rubella infection in a pregnant woman can result in serious
congenital abnormalities in the child. If the mother does not
have antibody, the virus can replicate in the placenta and
spread to the fetal blood supply and throughout the fetus.
Rubella can replicate in most tissues of the fetus. The virus

524 SECTION 5  •  Virology

Percent positive 100 BOX 52.4  Epidemiology of Rubella Virus

Virus in Disease/Viral Factors
80 pharynx
Rubella infects only humans.
Viremia Virus can cause asymptomatic disease.
There is one serotype. 
60
Rash Transmission

40 Lymphadenopathy Respiratory route 

Fever Who Is at Risk?
20
Children: mild exanthematous disease.
0 ؉6 ؉7 ؉11 ؉15 Adults: more severe disease with arthritis or arthralgia.
to to to Fetus <20 weeks: congenital defects. 
؊12 ؊9 ؊6 ؊3 0 ؉3
to ؉10 ؉14 ؉19 Modes of Control

؊10 Posteruption Live attenuated vaccine administered as part of the measles-
Prodrome mumps-rubella vaccine.

Onset of rash

Fig. 52.7  Time course of rubella disease. Rubella production in TABLE 52.3  Estimated Morbidity Associated with the
the pharynx precedes the appearance of symptoms and continues 1964–1965 U.S. Rubella Epidemic
throughout the course of the disease. The onset of lymphadenopathy
coincides with the viremia. Fever and rash occur later. The person is Clinical Events Number Affected
infectious as long as the virus is produced in the pharynx. (Modified
from Plotkin, S.A., Orenstein, W.A., Offit, P.A., 2008. Vaccines, fifth ed. Saun- Rubella cases 12,500,000
ders, Philadelphia, PA.) Arthritis-arthralgia 159,375

Presence of the virus during the development of the baby’s Encephalitis 2,084
immune response may even have a tolerogenic effect on
the system, preventing effective clearance of the virus after DEATHS 2,100
birth.   Excess neonatal deaths

 Other deaths 60

EPIDEMIOLOGY  Total deaths 2,160
Humans are the only host for rubella (Box 52.4). The virus
is spread in respiratory secretions and is generally acquired Excess fetal wastage 6,250
during childhood. Spread of virus, before or in the absence 8,055
of symptoms, and crowded conditions (e.g., day-care cen- CONGENITAL RUBELLA SYNDROME
ters) promote contagion.  Deaf children

Approximately 20% of women of childbearing age escape  Deaf/blind children 3,580
infection during childhood and are susceptible to infec-
tion unless vaccinated. Programs in many U.S. states test  Mentally retarded children 1,790
expectant mothers for antibodies to rubella.
 Other congenital rubella syndrome symptoms 6,575
Before the development and use of the rubella vaccine,
cases of rubella in schoolchildren would be reported every  Total congenital rubella syndrome 20,000
spring, and major epidemics of rubella occurred at regu-
lar 6- to 9-year intervals. The severity of the 1964–1965 Therapeutic abortions 5,000
epidemic in the United States is shown in Table 52.3. Con-
genital rubella occurred in as many as 1% of all the children From National Communicable Disease Center, 1969. Rubella surveillance, Report
born in cities such as Philadelphia during this epidemic. No. 1. U.S. Department of Health, Education, and Welfare, Washington, DC.
The immunization program has succeeded in eliminating
endemic rubella virus infection in the United States.  hypersensitivity reactions are a major cause of the more
severe forms of rubella in adults.
CLINICAL SYNDROMES
Rubella disease is normally benign in children. After a 14- Congenital disease is the most serious outcome of
to 21-day incubation period, the symptoms in children rubella infection. The fetus is at major risk until the 20th
consist of a 3-day maculopapular or macular rash and week of pregnancy. Maternal immunity to the virus result-
swollen glands (Fig. 52.8). Infection in adults, however, ing from prior exposure or vaccination prevents spread of
can be more severe and include problems such as bone and the virus to the fetus. The most common manifestations of
joint pain (arthralgia and arthritis) and (rarely) thrombocy- congenital rubella infection are cataracts, mental retarda-
topenia or postinfectious encephalopathy. Immunopatho- tion, cardiac abnormalities, and deafness (Boxes 52.5 and
logic effects resulting from cell-mediated immunity and 52.6; see Table 52.3). The mortality in utero and within the
first year after birth is high for affected babies. 

LABORATORY DIAGNOSIS
Isolation of the rubella virus is difficult and rarely attempted.
When isolation of the virus is necessary, the virus is usually

52  •  Togaviruses and Flaviviruses 525

Rubella cases per CRS cases per
100,000 population 100,000 live births
30

26 Rubella, total 14
Vaccine Rubella, Ն15-year-old 12
CRS
22 licensed

10

18

8

14

6

Fig. 52.8  Close-up of the rubella rash. Small erythematous macules 10
are visible. (From Hart, C.A., Broadwell, R.L., 1992. A Color Atlas of Pediatric 4
Infectious Disease. Wolfe, London, UK.)
6
BOX 52.5  Prominent Clinical Findings in 2
Congenital Rubella Syndrome
2
Cataracts and other ocular defects 0
Heart defects
Deafness 1966 68 70 72 74 76 78 80 82 84
Intrauterine growth retardation Year
Failure to thrive
Mortality within the first year Fig. 52.9  Effect of rubella virus vaccination on the incidence of rubella
Microcephaly and congenital rubella syndrome (CRS). (Modified from Williams, M.N.,
Mental retardation Preblud, S.R., 1984. Current trends: rubella and congenital rubella—United
States. Morbidity and Mortality Weekly Report 33, 237–247.)
BOX 52.6  Clinical Summaries
TREATMENT, PREVENTION, AND CONTROL
West Nile encephalitis: During August, a 70-year-old man from a No treatment is available for rubella. The best means of pre-
swampy area of Louisiana developed fever, headache, muscle venting rubella is vaccination with the live cold-adapted
weakness, nausea, and vomiting. He had difficulty answering RA27/3 vaccine strain of virus (Fig. 52.9). The live rubella
questions. He progressed into a coma. Magnetic resonance vaccine is usually administered with the measles and
imaging results show no specific localization of lesions (unlike mumps vaccines (MMR vaccine) after 12 months of age.
in herpes simplex virus encephalitis). His disease progressed to The triple vaccine is included routinely in well-baby care.
respiratory failure and death. His 25-year-old niece, living next Vaccination promotes both humoral and cellular immunity.
door, complained of sudden onset of fever (39° C [102.2° F]),
headache, and myalgias, with nausea and vomiting lasting 4 The primary reason for the rubella vaccination program
days. (See website https://doi.org/10.3810/pgm.2003.07.1456). is to prevent congenital infection by decreasing the number
of susceptible people in the population, especially children.
Yellow fever: A 42-year-old man had fever (103° F), headache, As a result, there are fewer seronegative mothers and a
vomiting, and backache that started 3 days after returning from smaller chance they will be exposed to the virus from con-
a trip to Central America. He appeared normal for a short time, tact with infectious children. Because only one serotype for
but then his gums started to bleed; he had bloody urine and rubella exists and humans are the only reservoir, vaccina-
vomited blood; and he developed petechiae, jaundice, and tion of a large proportion of the population can significantly
a slower and weakened pulse. He started to improve 10 days reduce the likelihood of exposure to the virus.
after the onset of disease.
  For a case study and questions see StudentConsult.com.
Rubella: A 6-year-old girl from Romania developed a faint rash
on her face, accompanied by mild fever and lymphadenopathy. Bibliography
Over the next 3 days, the rash progressed to other parts of the
body. She had no history of rubella immunization. Burrell, C.J., Howard, C.R., Murphy, F.A., 2017. Fenner and White’s Medi-
cal Virology 5e. Academic, Cambridge, MA.
obtained from urine. The virus can be detected by RT-PCR
of viral RNA. The diagnosis can be confirmed by the pres- Chambers, T.J., Hahn, C.S., Galler, R., et  al., 1990. Flavivirus genome
ence of antirubella-specific IgM. Antibodies to rubella are organization, expression, and replication. Annu. Rev. Microbiol. 44,
assayed early in pregnancy to determine the immune status 649–688.
of the woman; this test is required in many states. 
Chambers, T.J., Monath, T.P., 2003. The flaviviruses: detection, diagnosis,
and vaccine development, vol 61; The flaviviruses: pathogenesis and
immunity, vol 60. Adv. Virus Res. Elsevier Academic, San Diego.

Fernandez-Garcia, M.D., Mazzon, M., Jacobs, M., et al., 2009. Pathogen-
esis of flavivirus infections: using and abusing the host cell. Cell. Host.
Microbe. 5, 318–328.

Flint, S.J., Racaniello, V.R., et al., 2015. Principles of Virology, fourth ed.
American Society for Microbiology Press, Washington, DC.

Gelfand, M.S., 2003. West Nile virus infection. What you need to know
about this emerging threat. Postgrad. Med. 114, 31–38.

Gould, E.A., Solomon, T., 2008. Pathogenic flaviviruses. Lancet 371,
500–509.

526 SECTION 5  •  Virology

Guabiraba, R., Ryffel, B., 2014. Dengue virus infection: current concepts Richman, D.D., Whitley, R.J., Hayden, F.G., 2017. Clinical Virology,
in immune mechanisms and lessons from murine models. Immunology fourth ed. American Society for Microbiology Press, Washington, DC.
141, 143–156.
Rothman, A.L., 2010. Dengue Virus. Current Topics in Microbiol-
Halstead, S.B., Thomas, S.J., 2018. Dengue Virus. In: Plotkin, S.A., Oren- ogy and Immunology, vol 338. Springer-Verlag, Berlin. https://doi.
stein, W.A., Offit, P.A., Edwards, K.M. (Eds.), Vaccines, seventh ed. Else- org/10.1007/978-3-642-02215-9.
vier. Saunders, Philadelphia.
Staples, J.E., Monath, T.P., Gershman, M.D., Barrett, A.D.T., 2018. Yellow
Johnson, R.T., 1998. Viral Infections of the Nervous System. Lippincott- fever vaccine. In: Plotkin, S.A., Orenstein, W.A., Offit, P.A., Edwards,
Raven, Philadelphia. K.M. (Eds.), Vaccines, seventh ed. Elsevier, Philadelphia.

Knipe, D.M., Howley, P.M., 2013. Fields Virology, sixth ed. Lippincott Wil- Tyler, K.L., 2018. Acute viral encephalitis. N. Engl. J. Med. 379, 557–566.
liams & Wilkins, Philadelphia. https://doi.org/10.1056/NEJMra1708714.

Koblet, H., 1990. The “merry-go-round”: alphaviruses between vertebrate Websites
and invertebrate cells. Adv. Virus. Res. 38, 343–403. Centers for Disease Control. Vital Signs: Trends in Reported Vectorborne

Kuhn, R.J., Zhang, W., Rossmann, M.G., et al., 2002. Structure of dengue Disease Cases—United States and Territories, 2004–2016. https://www.
virus: implications for flavivirus organization, maturation, and fusion. cdc.gov/mmwr/volumes/67/wr/mm6717e1.htm. Accessed September
Cell 108, 717–725. 4, 2018.
Centers for Disease Control and Prevention: Division of Vector Borne
Mackenzie, J.S., Barrett, A.D.T., Deubel, V., 2002. ­Diseases. www.cdc.gov/ncezid/dvbd/. Accessed September 3, 2018.
Japanese Encephalitis and West Nile Viruses. Current Topics in Microbiol- Centers for Disease Control and Prevention: Chikungunya. https://www.
cdc.gov/chikungunya/. Accessed September 3, 2018.
ogy and Immunology, vol. 267. Springer-Verlag, Berlin. Centers for Disease Control and Prevention: Dengue. www.cdc.gov/dengue/.
Mukhopadhyay, S., Kim, B.S., Chipman, P.R., et  al., 2003. Structure of Accessed September 3, 2018.
Centers for Disease Control and Prevention: Dengue training modules.
West Nile virus. Science 302, 248. https://www.cdc.gov/dengue/training/cme/ccm/page32415.html.
Nash, D., Mostashari, F., Fine, A., et al., 2001. The outbreak of West Nile Accessed September 3, 2018.
Centers for Disease Control and Prevention: West Nile virus. www.cdc.gov/
virus infection in the New York City area in 1999. N. Engl. J. Med. 344, ncidod/dvbid/westnile/index.htm. Accessed September 3, 2018.
1807–1814. Centers for Disease Control and Prevention: Zika Virus. https://www.cdc.
Plotkin, S.A., Graham, B.S., 2018. Zika virus. In: Plotkin, S.A., Orenstein, gov/zika/index.html. Accessed September 3, 2018.
W.A., Offit, P.A., Edwards, K.M. (Eds.), Vaccines, seventh ed. Elsevier,
Philadelphia.
Plotkin, S.A., Reef, S., 2018. Rubella vaccine. In: Plotkin, S.A., Orenstein,
W.A., Offit, P.A., Edwards, K.M. (Eds.), Vaccines, seventh ed. Elsevier,
Philadelphia.

Case Studies and Questions Two weeks after returning from a trip to Pakistan, a 25-year-
old man had arthralgia (joint aches) and a mild rash that
A 27-year-old businessman experienced a high fever, started on his face and spread to his body. He recalled that
serious retroorbital headache, and severe joint and back he had felt as if he had the flu a few days before the onset of
pain 5 days after he and his family returned from a trip to the rash. The rash disappeared in 4 days.
Malaysia. The symptoms lasted for 4 days, and then a rash 5. What features of this case pointed to the diagnosis of
appeared on his palms and soles, which lasted for 2 days. At
the same time, the man’s 5-year-old son experienced mild rubella infection?
flulike symptoms and then collapsed after 2 to 5 days. The 6. Why is it significant that the symptoms started after a
boy’s hands were cold and clammy, his face was flushed,
and his body was warm. There were petechiae on his fore- trip outside the United States?
head and ecchymoses elsewhere. He bruised very easily. He 7. What precaution could the man have taken to prevent
was breathing rapidly and had a weak, rapid pulse. He then
rapidly recovered after 24 hours. this infection?
1 . What features of these cases pointed to the diagnosis of 8. How was this infection transmitted?
9. Who was at risk for a serious outcome of this infection?
dengue virus infection? 10. If this disease is normally mild in children, why is their
2 . Of what significance was the trip to Malaysia?
3. What was the source of infection in the father and son? immunization so important?
4. What were the significance of and the pathogenic basis

for the petechiae and ecchymoses in the child?

526.e1

53 Bunyaviridae and

Arenaviridae

A 50-year-old man was visiting family in Liberia and spleen. He began to cough up blood and then went
stayed in a house infested with rodents. He developed into shock and died.
severe flulike symptoms, a sore throat, and red eyes 1. How was this individual infected with Lassa fever virus?
and was treated with amoxicillin and chloroquine. 2 . What are the unique characteristics of arenaviruses?
His condition worsened, with increased fever, severe 3. How are they similar to bunyaviruses? How are they
headache, and swollen lymph nodes, tonsils, and
different?
  Answers to these questions are available on Student
Consult.com.

Summaries Clinically Significant Organisms

BUNYAVIRUSES Diagnosis ᑏᑏ Prodrome of flulike symptoms caused by
interferon and cytokine response
Trigger Words ᑏᑏ RT-PCR, ELISA
Treatment, Prevention, and Control ᑏᑏ LCM virus: meningitis
Arboviruses: mosquito, encephalitis ᑏᑏ Lassa fever: hemorrhagic fever
Hantaviruses: rodent, hemorrhagic disease ᑏᑏ Arboviruses: mosquito control
ᑏᑏ Hantaviruses: rodent control Epidemiology
Biology, Virulence, and Disease
ARENAVIRUSES ᑏᑏ Inhalation of aerosols from rodent urine
ᑏᑏ Medium size, enveloped, (−) segmented Trigger Words or feces
RNA genome
ᑏᑏ Ribosomes in virion, rodent, Lassa fever ᑏᑏ LCM virus: worldwide
ᑏᑏ Encodes RNA-dependent RNA poly- virus, hemorrhagic disease, LCM virus, ᑏᑏ Lassa fever: Africa
merase, replicates in cytoplasm meningitis
Diagnosis
ᑏᑏ Antibody can block disease Biology, Virulence, and Disease
ᑏᑏ Virus spreads in blood to tissues, neurons, ᑏᑏ RT-PCR, ELISA
ᑏᑏ Medium size, enveloped, (−) segmented
and brain RNA genome Treatment, Prevention, and Control
ᑏᑏ Prodrome of flulike symptoms caused by
ᑏᑏ Nonfunctional ribosomes in virion ᑏᑏ Rodent control
interferon and cytokine response ᑏᑏ Encodes RNA-dependent RNA poly-
ᑏᑏ Encephalitis: La Crosse, California
merase, replicates in cytoplasm
encephalitis ᑏᑏ Antibody can block disease
ᑏᑏ Hantaviruses: pulmonary syndrome ᑏᑏ Virus spreads in blood to tissues, neurons,

Epidemiology and brain

ᑏᑏ Encephalitis viruses: zoonosis, reservoir in
birds, vector is the mosquito

ᑏᑏ Hantavirus: inhalation of aerosols from
rodent urine or feces

ELISA, Enzyme-linked immunosorbent assay; LCM, lymphocytic choriomeningitis, RT-PCR, reverse transcriptase-polymerase chain reaction.

The Bunyaviridae and Arenaviridae share several similari- by mosquitoes, ticks, or flies and are endemic to the envi-
ties. The viruses of these families are negative-strand ribo- ronment of the vector. The hantaviruses are the excep-
nucleic acid (RNA)-enveloped viruses with similar modes of tion; they are carried by rodents. New human viruses are
replication. Both are zoonoses; most of the Bunyaviridae are still being discovered, including the tick-borne Heartland
arboviruses. The hantaviruses and Arenaviridae are spread phlebovirus in the United States in 2012. In 2011, the tick-
by rodents and not insects. Many of the viruses from these borne severe fever with thrombocytopenia syndrome virus
families cause encephalitis or hemorrhagic disease. (SFTSV) was discovered in China.

Bunyaviridae STRUCTURE
The bunyaviruses are roughly spherical particles 90 to 120
The Bunyaviridae constitute a “supergroup” of at least 200 nm in diameter. The envelope of the virus contains two
enveloped, segmented, negative-strand RNA viruses glycoproteins (G1 and G2) and encloses three unique nega-
(Box 53.1). The supergroup of mammalian viruses is fur- tive-strand RNAs, the large (L), medium (M), and small (S)
ther broken down into genera on the basis of structural RNAs that are associated with protein to form nucleocap-
and biochemical features: Bunyavirus, Phlebovirus, Nairo- sids (Table 53.2). The genome segments for the La Crosse
virus, and Hantavirus (Table 53.1). Most of the Bunyaviri- and related California encephalitis viruses form circles. The
dae are arboviruses (arthropod-borne) that are spread nucleocapsids include the RNA-dependent RNA polymerase

527

528 SECTION 5  •  Virology

BOX 53.1  Unique Features of Bunyaviruses the bunyaviruses are good inducers of type 1 interferons.
Bunyavirus disease is caused by a combination of immune
There are at least 200 related viruses in five genera that share a and viral pathogenesis.
common morphology and basic components.
Unlike the other bunyaviruses, rodents are the reservoir
Virion is enveloped with three (L, M, S) negative-sense ribonucleic and vector for hantaviruses, and humans acquire the virus by
acid nucleocapsids but no matrix proteins. breathing aerosols contaminated with infected urine. Hanta-
viruses target the kidneys and cause chronic asymptomatic
Virus replicates in the cytoplasm. infection in rodents, which leads to long-term viral shedding
Virus can infect humans, animals, and arthropods. in urine. Human inhalation brings the virus to the lungs, and
Virus in an arthropod can be transmitted to its eggs. then it can spread to the vasculature and kidneys, in which it
replicates but is not cytolytic. It disrupts endothelial cell func-
(L protein) and two nonstructural proteins (NSs, NSm) (Fig. tion, causing vascular permeability, which can lead to shock
53.1). Unlike other negative-strand RNA viruses, the Bun- and induces cytolytic immune responses to cause hemor-
yaviridae do not have a matrix protein. The genera of rhagic tissue destruction and lethal pulmonary disease. 
Bunyaviridae are distinguished by differences in (1) the
number and sizes of the virion proteins; (2) the lengths of EPIDEMIOLOGY
the L, M, and S strands of the genome; and (3) how they are Most bunyaviruses are transmitted by infected mosquitoes,
transcribed.  ticks, or Phlebotomus flies to rodents, birds, and larger ani-
mals (Box 53.3). The animals then become the reservoirs
REPLICATION for the virus, continuing the cycle of infection. Humans are
The Bunyaviridae replicate in the same way as other envel- infected when they enter the environment of the insect vec-
oped negative-strand RNA viruses. For most Bunyaviridae, tor (Fig. 53.2) but are usually dead-end hosts. Transmission
the G1 glycoprotein interacts with β-integrins on the cell sur- occurs during the summer, but unlike many other arbovi-
face, and the virus is internalized by endocytosis. After fusion ruses, many of the Bunyaviridae can survive a winter in the
of the envelope with endosomal membranes on acidification mosquito eggs and remain in a locale.
of the vesicle, the nucleocapsid is released into the cyto-
plasm, and messenger RNA (mRNA) and protein synthesis Many of the members of this virus family are found in
begin. Like influenza, the bunyaviruses steal the 5′-capped South America, southeastern Europe, Southeast Asia, and
portion of mRNAs to prime the synthesis of viral mRNAs; Africa and bear the exotic names of their ecologic niches.
but unlike influenza, this occurs in the cytoplasm. Separate Viruses of the California encephalitis virus group (e.g.,
positive-strand templates are used to replicate the genome. La Crosse virus) are spread by mosquitoes found in the forests
of North America (Fig. 53.3). Up to 100 cases of encephali-
The M strand encodes the NSm nonstructural protein and tis are reported during the summer each year in the United
the G1 (viral attachment) and G2 proteins, and the L strand States, but most infections are asymptomatic. These viruses
encodes the L protein (polymerase) (see Table 53.2). The S are spread mainly by aggressive day-biting Aedes triseriatus,
strand of RNA encodes two nonstructural proteins, N and which breeds in the water in tree holes and in discarded tires.
NSs. For the Phlebovirus group, the S strand is ambisense,
such that one mRNA is transcribed from the genome and The hantaviruses do not have an arthropod vector but
the other from the (+) RNA template for replication. are maintained in a rodent species specific for each virus.
Humans are infected by close contact with rodents or
The glycoproteins are synthesized and glycosylated in through inhalation of aerosolized rodent urine. In May 1993,
the endoplasmic reticulum, after which they are trans- a deadly outbreak of hantavirus pulmonary syndrome
ferred to the Golgi apparatus but not translocated to the (HPS) occurred in the Four Corners area of New Mexico.
plasma membrane. Virions are assembled by budding The outbreak is attributed to increased contact with the deer
into the Golgi apparatus and are released by cell lysis or mouse vector during a season of unusually high rainfall,
exocytosis.  greater availability of food, and a rise in the rodent popula-
tion. Viruses of the Sin Nombre subfamily were isolated from
PATHOGENESIS the victims and rodents. Since this incident, viruses from this
Most of the Bunyaviridae are arboviruses and possess many subfamily have been detected and associated with outbreaks
of the same pathogenic mechanisms as the togaviruses and of respiratory tract disease in the eastern and western United
flaviviruses (Box 53.2). For example, the viruses are spread States and in Central and South America. 
by an arthropod vector and are injected into the blood to
initiate a viremia. Progression past this stage to secondary CLINICAL SYNDROMES
viremia and further dissemination of the virus can deliver Bunyaviridae, even those that can cause serious disease,
the virus to target sites such as the central nervous sys- usually cause relatively mild nonspecific febrile, flulike,
tem, liver, kidney, and vascular endothelium to cause dis- viremia-related illness (Clinical Case 53.1; see Table 53.1)
ease. Many Bunyaviridae cause encephalitis; others cause that is indistinguishable from illnesses caused by other
hepatic necrosis or hemorrhagic disease (e.g., Crimean- viruses. The incubation period for these illnesses is approxi-
Congo hemorrhagic fever and Hantaan hemorrhagic dis- mately 48 hours, and the fevers typically last 3 days.
ease) in ways similar to the toga and flaviviruses. In the
latter infection, hemorrhagic necrosis of the kidney occurs Encephalitis illnesses (e.g., La Crosse virus) are sud-
often. Like togaviruses, flaviviruses, and arenaviruses, den in onset after an incubation period of approximately 1
week, and symptoms at this time consist of fever, headache,

53  •  Bunyaviridae and Arenaviridae 529

TABLE 53.1  Notable Bunyaviridae Generaa

Genus Members Insect Vector Pathologic Conditions Vertebrate Hosts

Bunyavirus Bunyamwera virus, California encephalitis Mosquito Febrile illness, encephalitis, Rodents, small mammals,
Phlebovirus virus, La Crosse virus, Oropouche virus; Fly, tick rash primates, marsupials, birds
150 members
Sandfly fever, hemorrhagic Sheep, cattle, domestic animals
Rift Valley fever virus, sandfly fever virus, fever, encephalitis, conjunc-
Heartland virus; 38 members tivitis, myositis

Nairovirus Crimean-Congo hemorrhagic fever virus; 6 Tick Hemorrhagic fever Hares, cattle, goats, seabirds
members

Uukuvirus Uukuniemi virus; 7 members Tick — Birds

Hantavirus Old World; Hantaan virus and others None Hemorrhagic fever with renal Rodents
New World; Sin Nombre and others None syndrome, adult respiratory Rodents
distress syndrome

Hantavirus pulmonary syn-
drome, shock, pulmonary
edema

aAdditional viruses possess several common properties with Bunyaviridae but are as yet unclassified.

TABLE 53.2  Genome and Proteins of California viremia (e.g., Rift Valley fever, HFRS, Crimean-Congo hem-
Encephalitis Virus orrhagic fever) or from mosquitoes. 
Genomea Proteins
L RNA polymerase, 170 kDa TREATMENT, PREVENTION, AND CONTROL
M G1 glycoprotein, 75 kDa No specific therapy for infections of the Bunyaviridae is
available. Human disease is prevented by interruption
G2 glycoprotein, 65 kDa of the contact between humans and the vector, whether
NSm (nonstructural) protein, 15–17 kDa arthropod or mammal. Arthropod vectors are controlled
S N (nonstructural) protein, 25 kDa by (1) eliminating the growth conditions for the vector, (2)
NSs (nonstructural) protein, 10 kDa spraying with insecticide, (3) installing netting or screening
at windows and doors, (4) wearing protective clothing, and
aNegative-strand RNA. (5) controlling the tick infestation of animals. Rodent con-
trol minimizes the transmission of hantaviruses. 
lethargy, and vomiting. Seizures occur in 50% of patients
with encephalitis, usually early in the illness. Signs of men- Arenaviruses
ingitis may also be present. The illness lasts 10 to 14 days.
Death occurs in less than 1% of patients, but seizure disor- The arenaviruses include lymphocytic choriomeningi-
ders may occur as sequelae in as many as 20%. tis (LCM) and hemorrhagic fever viruses, such as the
Lassa, Junin, and Machupo viruses (Box 53.4). These
Hemorrhagic fevers such as Rift Valley fever are char- viruses cause persistent infections in specific rodents and
acterized by petechial hemorrhages, ecchymosis, epistaxis, can be transmitted to humans as zoonoses.
hematemesis, melena, and bleeding of the gums. Death
occurs in as many as half of patients with hemorrhagic STRUCTURE AND REPLICATION
disease. HPS occurs in the Americas and is a terrible dis- Arenaviruses are seen in electron micrographs as pleomor-
ease, manifesting initially as a prodrome of fever, flulike phic enveloped viruses (diameter, 120 nm) that have a
symptoms, and muscle aches but followed rapidly by inter- sandy appearance (the name comes from the Greek word
stitial pulmonary edema, respiratory failure, shock, and arenosa, meaning “sandy”) because of the ribosomes
death within days. Hemorrhagic fever with renal syndrome in the virion. Although functional, the ribosomes do not
(HFRS) occurs in Europe and Asia and adds petechial rash, seem to serve a purpose. Virions contain a nucleocapsid
systemic hemorrhagic disease, and kidney failure to HPS.  with two single-stranded RNA circles (S, 3400 nucleo-
tides; L, 7200 nucleotides) and a transcriptase. The L strand
LABORATORY DIAGNOSIS is a negative-sense RNA and encodes the polymerase. The
Detection of viral RNA by reverse transcriptase-polymerase S strand encodes the nucleoprotein (N protein) and the
chain reaction (RT-PCR) has become the accepted method glycoproteins but is ambisense. Whereas the mRNA for
for detecting and identifying bunyaviruses. The Sin Nom- the N protein is transcribed directly from the ambisense S
bre and Convict Creek hantaviruses were initially identified strand, the mRNA for the glycoprotein is transcribed from
with the RT-PCR test, using primers with characteristic a full-length template of the S strand. Like togaviruses, the
hantavirus sequences. glycoproteins are produced as late proteins after genome

Enzyme-linked immunosorbent assay (ELISA) may detect
antigen in clinical specimens from patients with an intense

530 SECTION 5  •  Virology

Glycoprotein L3
(5-10 nm spikes) L
Lipid
envelope 1

Nucleocapsids 2
L

1. L RNA B
2. M RNA
3. S RNA

A L polymerase

Fig. 53.1  (A) Model of the bunyavirus particle. (B) Electron micrograph of La Crosse variant of bunyavirus. Note the spike proteins at the surface of the
virion envelope. RNA, Ribonucleic acid. (A, Modified from Fraenkel-Conrat, H., Wagner, R.R., 1979. Comprehensive Virology, vol. 14. Plenum, New York, NY. B,
Courtesy Centers for Disease Control and Prevention, Atlanta, Georgia.)

BOX 53.2  Disease Mechanisms for Aedes triseriatus
Bunyaviruses
Squirrel Transovarial Human
Virus is acquired from an arthropod bite (e.g., mosquito). (chipmunk) transmission
For hantaviruses, the virus is acquired from rodent urine or feces.
Initial viremia causes flulike symptoms.
Establishment of secondary viremia may allow virus access to

specific target tissues that define the disease, including the
central nervous system, organs, and vascular endothelium.
Viral and immunopathogenesis causes tissue disruption.
Antibody is important in controlling viremia; interferon and
cell-mediated immunity may prevent the outgrowth of
infection and contribute to disease.

Fig. 53.2  Transmission of La Crosse (California) encephalitis virus.

BOX 53.3  Epidemiology of Bunyavirus MN
Infections 286 WI NY
415 MI 50
Disease/Viral Factors 13 PA
IA
Arboviruses able to replicate in mammalian and arthropod cells. 98 OH 6
Arboviruses able to pass into ovary and infect arthropod eggs, CA MO ILL IN 631
1 12 145 114 VA
allowing virus to survive during winter.  AR MS 1
KY NC 38
Transmission 5 1 4 SC
LA 2
Arboviruses, via arthropod’s blood meal; California encephalitis OK TN 8
group, Aedes mosquito; 2
GA
Aedes mosquitoes are aggressive daytime feeders and live in 11
forests.
12
Aedes mosquitoes lay eggs in small pools of water trapped in
places such as trees and tires. WV CN NJ DE MD D.C.
57 1 3 1 1 9
Hantavirus: transmitted in aerosols from rodent urine and feces
and by close contact with infected rodents.  Fig. 53.3  Distribution of California encephalitis, 1964 to 2010. (Cour-
tesy Centers for Disease Control and Prevention, Atlanta, Georgia.)
Who Is at Risk?
replication. Arenaviruses replicate in the cytoplasm and
People in habitat of arthropod or rodent vector. acquire their envelope by budding from the host cell plasma
California encephalitis group: campers, forest rangers, woodsmen.  membrane.

Geography/Season Arenaviruses readily cause persistent infections. This
may result from inefficient transcription of the glycoprotein
Disease incidence correlates with distribution of vector. genes and thus poor virion assembly. 
Disease more common in summer. 

Modes of Control

Elimination of vector or vector’s habitat.
Avoidance of vector’s habitat.

53  •  Bunyaviridae and Arenaviridae 531

Clinical Case 53.1  Hantavirus in BOX 53.5  Clinical Summary
Virginia
Lassa fever: Approximately 10 days after returning from a trip
The Centers for Disease Control and Prevention (Morb to visit family in Nigeria, a 47-year-old man developed flulike
Mortal Wkly Rep 53:1086–1089, 2004) reported a case symptoms with a higher than expected fever and malaise. The
of hantavirus in a 32-year-old wildlife sciences graduate disease got progressively worse, and after 3 days, the patient
student. The patient visited the ED in Blacksburg, Virginia, developed abdominal pain, nausea, vomiting, diarrhea, pharyn-
after experiencing fever, cough, and a “sore chest.” The gitis, bleeding gums, and began vomiting blood. He developed
student had been trapping, handling, and studying mice shock and then died.
during the previous month. Neither he nor his colleagues
wore gloves while handling the mice or their excreta; consumption of contaminated food, or contact with fomi-
they did not wash before eating and had numerous mouse tes. Animal bites are not a usual mechanism of spread.
bites on their hands. He had a fever of 39.3° C and normal
lung function, but a chest radiograph indicated a faint The virus that causes LCM infects hamsters and house mice
right-sided pneumonia. The man started vomiting in the (Mus musculus). It was found in 20% of mice in Washington,
ED and was admitted. The pneumonia progressed, and he DC. Lassa fever virus infects Mastomys natalensis, which is an
became more hypoxic, eventually requiring intubation African rodent. The Lassa fever virus is spread from human
and mechanical ventilation. On the next day, he was given to human through contact with infected secretions or body
activated protein C to prevent disseminated intravascular fluids, but the viruses that cause LCM and other hemorrhagic
coagulation. The patient continued to fail and died on the fevers are rarely, if ever, spread in this way.
third day after hospitalization. Serum specimens con-
tained IgM and IgG antibody and genomic ribonucleic acid From 1999 to 2000, three cases of fatal hemorrhagic
(determined by reverse transcriptase-polymerase chain disease in California were found to be caused by the White-
reaction) to hantavirus, and viral antigens were present in water Arroyo arenavirus. This virus is normally found in
the spleen. Although the hantavirus received its great- the white-throated wood rat, so its occurrence in humans
est notoriety with the Sin Nombre virus outbreak in the constitutes a newly emergent disease. The disease associa-
southwestern United States in 1993, it can occur wherever tion was made by a special RT-PCR assay. 
people come in contact with the urine and feces of rodents
carrying these viruses. Cases have been reported in 31 of CLINICAL SYNDROMES
the United States. Lymphocytic Choriomeningitis
The name of this virus, lymphocytic choriomeningitis
ED, Emergency Department; Ig, immunoglobulin. virus, suggests that meningitis is a typical clinical event,
but actually, LCM usually causes a febrile illness with flu-
BOX 53.4  Characteristics of Arenaviruses like myalgia (Box 53.5). Only about 10% of infected persons
progress to a central nervous system infection. The menin-
Virus has enveloped virion with two circular, negative-RNA geal illness, if it occurs, will start 10 days after the initial
genome segments (L, S). Virion appears sandy because of phase of illness, with full recovery. Perivascular mononu-
ribosomes. clear infiltrates may be seen in neurons of all sections of the
brain and in the meninges of an affected patient. 
S genome segment is ambisense. Lassa and Other Hemorrhagic Fevers
Arenaviruses are zoonoses, establishing persistent infections in Lassa fever, which is endemic to West Africa, is the best
known of the hemorrhagic fevers caused by an arenavi-
rodents. rus. Other agents, however, such as the Junin and Mach-
Pathogenesis of arenavirus infections is largely attributed to upo viruses, cause similar syndromes in the inhabitants of
Argentina and Bolivia, respectively.
immunopathogenesis.
Clinical illness is characterized by fever, coagulopathy,
PATHOGENESIS petechiae, and occasional visceral hemorrhage, as well as by
Arenaviruses are able to infect macrophages, induce cyto- liver and spleen necrosis, but not vasculitis. Hemorrhage and
kine and interferon release, and promote cell and vascular shock also occur, as does occasional cardiac and liver dam-
damage. T-cell–induced immunopathologic effects signifi- age. In contrast to LCM, hemorrhagic fevers cause no lesions
cantly exacerbate tissue destruction. The incubation period in the central nervous system. Pharyngitis, diarrhea, and
for arenavirus infections averages 10 to 14 days.  vomiting may be prevalent, especially in patients with Lassa
fever. Death occurs in as many as 50% of those with Lassa
EPIDEMIOLOGY fever and in a smaller percentage of those infected with the
Most arenaviruses, except for the virus that causes LCM, are other arenaviruses that cause hemorrhagic fevers. The diag-
found in the tropics of Africa and South America. The are- nosis is suggested by recent travel to endemic areas. 
naviruses, like the hantaviruses, infect specific rodents and
are endemic to the rodents’ habitats. Chronic asymptom- LABORATORY DIAGNOSIS
atic infection is common in these animals and leads to long- An arenavirus infection is usually diagnosed on the basis
term viral shedding in saliva, urine, and feces. Humans of serologic and genomic (RT-PCR) findings. These viruses
may become infected through inhalation of aerosols, are too dangerous for isolation. Throat specimens can yield

532 SECTION 5  •  Virology

arenaviruses; urine is a source for the Lassa fever virus Gonzalez, J.P., et al., 2007. Arenaviruses, Current Topics in Microbiology
but not for the LCM virus. The risk of infection is substan- and Immunology, vol. 315. Springer-Verlag, Berlin, pp. 253–288.
tial for laboratory workers handling body fluids. Therefore
if the diagnosis is suspected, laboratory personnel should Johnson, R.T., 1998. Viral Infections of the Nervous System. Lippincott-
be so warned and the specimens processed only in facili- Raven, Philadelphia.
ties that specialize in the isolation of contagious pathogens
(level 3 for LCM and level 4 for Lassa fever and other Knipe, D.M., Howley, P.M., 2013. Fields Virology, sixth ed. Lippincott Wil-
arenaviruses).  liams & Wilkins, Philadelphia.

TREATMENT, PREVENTION, AND CONTROL Kolakofsky, D., 1991. Bunyaviridae. Current Topics in Microbiology and
The antiviral drug ribavirin has limited activity against Immunology, vol. 169. Springer-Verlag, Berlin.
arenaviruses and can be used to treat Lassa fever. How-
ever, supportive therapy is usually all that is available for Oldstone, M.B.A., 2002. Arenaviruses I and II, Current Topics in Microbi-
patients with arenavirus infections. ology and Immunology, vol. 262–263, Berlin, Springer-Verlag.

These rodent-borne infections can be prevented by limit- Peters, C.J., Simpson, G.L., Levy, H., 1999. Spectrum of hantavirus infec-
ing contact with the vector. For example, improved hygiene tion: hemorrhagic fever with renal syndrome and hantavirus pulmo-
to limit contact with mice reduced the incidence of LCM in nary syndrome. Annu. Rev. Med. 50, 531–545.
Washington, DC. In the geographic areas in which hemor-
rhagic fever occurs, trapping rodents and carefully storing Schmaljohn, C.S., Nichol, S.T., 2001. Hantaviruses, Current Topics in
food may decrease exposure to the virus. Microbiology and Immunology, vol. 256. Springer-Verlag, Berlin.

The incidence of laboratory-acquired cases can be Strauss, J.M., Strauss, E.G., 2007. Viruses and Human Disease, second ed.
reduced if samples submitted for arenavirus isolation are Academic, San Diego.
processed in at least level 3 or level 4 biosafety facilities and
not in the usual clinical virology laboratory. Tsai, T.F., 1991. Arboviral infections in the United States. Infect. Dis. Clin.
North. Am. 5, 73–102.
  For a case study and questions see StudentConsult.com.
Tyler, K.L., 2018. Acute viral encephalitis. N. Engl. J. Med. 379, 557–566.
Bibliography https://doi.org/10.1056/NEJMra1708714.

Avšič-Županc, T., Saksida, A., Korva, M., 2016. Hantavirus infections. Walter, C.T., Barr, J.N., 2011. Recent advances in the molecular and
Clin. Microbiol. Infect. https://doi.org/ 10.1111/1469-0691.12291. cellular biology of bunyaviruses. J. Gen. Virol. 92, 2467–2484.
http://vir.sgmjournals.org/content/early/2011/08/22/vir.0.035105-
Bishop, D.H.L., Shope, R.E., 1979. Bunyaviridae. Plenum, New York. 0.full.pdf+html.
Burrell, C.J., Howard, C.R., Murphy, F.A., 2017. Fenner and White’s Medi-
Wrobel, S., 1995. Serendipity, science, and a new hantavirus. FASEB J. 9,
cal Virology 5e. Academic, Cambridge, MA. 1247–1254.
Cohen, J., Powderly, W.G., 2004. Infectious Diseases, second ed. Mosby,
Websites
St Louis. Ayoade, F.O., California encephalitis. http://emedicine.medscape.com/art

icle/234159-overview. Accessed September 4, 2018.
Centers for Disease Control and Prevention, Hantavirus. www.cdc.gov/ha

ntavirus/index.html. Accessed September 4, 2018.
Centers for Disease Control and Prevention, Heartland virus. www.cdc.go

v/ncezid/dvbd/heartland/index.html. Accessed September 4, 2018.
Centers for Disease Control and Prevention, La Crosse encephalitis. www.c

dc.gov/lac/. Accessed September 4, 2018.
Centers for Disease Control and Prevention, Lassa fever. www.cdc.gov/vhf

/lassa/. Accessed September 4, 2018.
Centers for Disease Control and Prevention, Lymphocytic choriomeningi-

tis (LCMV). www.cdc.gov/vhf/lcm/. Accessed September 4, 2018.
Gompf, S.G., Smith, K.M., Choe, U., Arenaviruses. http://emedicine.medsc

ape.com/article/212356-overview. Accessed September 4, 2018.

Case Studies and Questions fluid revealed inflammatory cells. She became lethargic over
the next day but became alert again after 4 to 5 days.
A 58-year-old woman complained of flulike symptoms, 4 . The physician suspected La Crosse encephalitis virus as
severe headache, stiff neck, and photophobia. She was
lethargic and had a mild fever. The cerebrospinal fluid spec- the agent. What clues pointed to La Crosse virus?
imen contained 900 white blood cells per milliliter, mostly 5 . What other agents would also be considered in the dif-
lymphocytes, and LCM virus. She recovered after a week.
Her home was infested with gray mice (M. musculus). ferential diagnosis?
1 . What were the significant symptoms of this disease? 6. How was the patient infected?
2 . How was the virus transmitted? 7 . How would transmission of this agent be prevented?
3 . What type of immune response is most important in 8 . How could the local public health department determine

controlling this infection? the prevalence of La Crosse virus in the environment of
A 15-year-old summer camp counselor in Ohio suddenly the summer camp? What samples would they obtain,
complained of headache, nausea, and vomiting; she had a and how would they test them?
fever and experienced a stiff neck. She was admitted to the hos-
pital, in which a spinal tap and examination of c­ erebrospinal

532.e1

54 Retroviruses

A 63-year-old woman has tuberculosis and a severe 3. To what other opportunistic infections is this woman
oral Candida yeast infection. Her CD4 T-cell level was susceptible?
50/μL, and 200,000 human immunodeficiency virus
(HIV) genomes per milliliter of blood were detected. 4 . What are risk factors for infection?
Although monogamous, she finds out that her hus- 5 . How was the HIV infection detected and how was
band was not.
1 . What cell types does HIV infect, and why does this have compliance to treatment followed?
6 . How can the HIV infection be treated?
such an effect on the patient’s immune response?
2. How does the virus replicate?   Answers to these questions are available on Student
Consult.com.

Summaries  Clinically Significant Organisms

RETROVIRUSES ᑏᑏ Causes syncytia Epidemiology
ᑏᑏ Incapacitates and escapes immune
Trigger Words ᑏᑏ Worldwide
control ᑏᑏ Transmitted in blood and semen
Reverse transcriptase, integration, syncytia ᑏᑏ Oncornaviruses may encode oncogene ᑏᑏ High-risk groups: promiscuous individu-
HIV: AIDS, CD4, chemokine co-receptor,
and have a short latency period before als, IV drug users, infants of infected
opportunistic diseases cancer mothers
HTLV: leukemia, flower cell, CD4 T cell ᑏᑏ HTLV-1, no oncogene, long latency
period before leukemia Diagnosis
Biology, Virulence, and Disease ᑏᑏ HTLV: acute T-cell lymphocytic leukemia,
tropical spastic paraparesis ᑏᑏ RT-PCR, ELISA
ᑏᑏ Virion: medium size, envelope, nucleocapsid, ᑏᑏ HIV: initially infects CD4/CCR5 macro-
two copies of (+) RNA genome phages, dendritic cells, and T cells; initial Treatment, Prevention, and Control
disease phase resembles mononucleosis
ᑏᑏ Simple retroviruses have three genes: followed by latent period; AIDS results ᑏᑏ HIV treatment with nucleoside analogs,
gag, pol, env when CD4 T cells drop below 200/μL protease inhibitors, and other antiviral
ᑏᑏ Endogenous retroviruses: integrated drugs
ᑏᑏ Complex retroviruses (HIV, HTLV) have and approximately 8% of human
gag, pol, env, and other important genes genome ᑏᑏ Prevention by screening of blood sup-
ply, safe sex, antiviral drug prophylaxis,
ᑏᑏ Encodes RNA-dependent DNA poly- education
merase (RT), replicates in nucleus

ᑏᑏ Virion carries RT, integrase, and protease
enzymes

ᑏᑏ Replicates through DNA intermediate, inte-
grates viral DNA into host chromosome

ELISA, Enzyme-linked immunosorbent assay; HTLV, human T-cell lymphotropic virus; IV, intravenous; RT-PCR, reverse transcriptase-polymerase chain reaction.

The retroviruses are probably the most studied group have since been isolated from other animal species and
of viruses in molecular biology. These viruses are are classified as RNA tumor viruses or oncornavi-
enveloped positive-strand ribonucleic acid (RNA) ruses. Many of these viruses alter cellular growth by
viruses with a unique morphology and means of repli- expressing analogs of cellular growth-controlling genes
cation. In 1970, Baltimore and Temin showed that the (oncogenes). Not until 1981, however, when Robert
retroviruses encode an RNA-dependent deoxyribo- Gallo and his associates isolated human T-cell lym-
nucleic acid (DNA) polymerase (reverse transcrip- photropic virus 1 (HTLV-1) from a person with adult
tase [RT]) and replicate through a DNA intermediate. human T-cell leukemia, was a human retrovirus associ-
The DNA copy of the viral genome is then integrated ated with human disease.
into the host chromosome to become a cellular gene.
This discovery, which earned Baltimore, Temin, and In the late 1970s and early 1980s, an unusual num-
Dulbecco the 1975 Nobel Prize, contradicted what had ber of young homosexual men, Haitians, heroin addicts,
been the central dogma of molecular biology—that and hemophiliacs in the United States (the initial “4H
genetic information passed from DNA to RNA and then club” of risk groups) were noted to be dying of normally
to protein. benign opportunistic infections. Their symptoms defined
a new disease, called acquired immunodeficiency
The first retrovirus to be isolated was the Rous sar- syndrome (AIDS). However, as is now known, AIDS
coma virus, shown by Peyton Rous to produce solid is not limited to these groups but can occur in anyone
tumors (sarcomas) in chickens. Like most retroviruses, exposed to the virus. Now approximately 37 million men,
the Rous sarcoma virus proved to have a very limited women, and children around the world are living with
host and species range. Cancer-causing retroviruses the virus that causes AIDS. Montagnier and associates

533

534 SECTION 5  •  Virology

in Paris, and Gallo and colleagues in the United States, distinct cytopathologic effect but, as already noted, do not
reported the isolation of the human immunodeficiency seem to cause clinical disease. 
virus (HIV-1) from patients with lymphadenopathy and
AIDS. A closely related virus, designated HIV-2, was iso- Structure
lated later and is prevalent in West Africa. HIV appears
to have been acquired by humans from chimpanzees and The retroviruses are roughly spherical, enveloped, RNA
then rapidly spread through Africa and the world by an viruses with a diameter of 80 to 120 nm (Fig. 54.2 and
increasingly mobile population. Although a devastating Box 54.1). The envelope contains viral glycoproteins and
disease that cannot be completely cured, the develop- is acquired by budding from the plasma membrane. The
ment of antiviral drug cocktails (highly active antiretro- envelope surrounds a capsid that contains two iden-
viral therapy [HAART]) has allowed many HIV patients tical copies of the positive-strand RNA genome inside
to resume a normal life. an electron-dense core. The virion also contains 10 to 50
copies of the RT and integrase enzymes and two cellu-
Endogenous retroviruses, the ultimate parasites, are lar transfer RNA (tRNAs). These tRNAs are base-paired
integrated, are transmitted vertically, and may take up as to each copy of the genome to be used as a primer for the
much as 8% of the human chromosome. Although they RT. The morphology of the core differs for different viruses
may not produce virions, they may still contribute to or and is used as a means of classifying the retroviruses (see
influence functions of the body. Fig. 54.1). The HIV virion core resembles a truncated cone
(Fig. 54.3).
Our understanding of the retroviruses has paralleled prog-
ress in molecular biology and immunology. In turn, the ret- The genome of the simple retroviruses consists
roviruses have provided a major tool for molecular biology, of three major genes that encode polyproteins for the fol-
the RT enzyme, and through the study of viral oncogenes lowing enzymatic and structural proteins of the
also have provided a means of advancing our understand- virus: Gag (group-specific antigen, capsid, matrix, and
ing of cell growth, differentiation, and oncogenesis. nucleic acid–binding proteins), Pol (polymerase, prote-
ase, and integrase), and Env (envelope, glycoproteins)
The three subfamilies of human retroviruses are the (Fig. 54.4 and Table 54.2). At each end of the genome
Oncovirinae (HTLV-1, HTLV-2, HTLV-5), the Lentiviri- are long terminal repeat (LTR) sequences. The LTR
nae (HIV-1, HIV-2), and the Spumavirinae (Table 54.1). sequences contain promoters, enhancers, and other
Although a spumavirus was the first human retrovirus to gene sequences used for binding different cellular tran-
be isolated, no such virus has been associated with human scription factors. Oncogenic viruses may also con-
disease. tain a growth-promoting oncogene. The complex
retroviruses, including HTLV, HIV, and other lentivi-
Classification ruses, express early and late proteins and encode several
virulence-enhancing proteins that require more complex
The retroviruses are classified by the diseases they cause, transcriptional processing (splicing) than the simple ret-
tissue tropism and host range, virion morphology, and roviruses. Although the genome resembles a messenger
genetic complexity (see Table 54.1). The oncoviruses RNA (mRNA), unlike a picornavirus genome, it is not
include the only retroviruses that can immortalize or infectious because the RT and integrase carried within
transform target cells. These viruses are also categorized the virion are required for replication.
by the morphology of their core and capsid as type A, B, C,
or D, as seen in electron micrographs (Fig. 54.1; see Table The viral glycoproteins are produced by proteolytic
54.1). The lentiviruses are slow viruses associated cleavage of the polyprotein encoded by the env gene. The
with neurologic and immunosuppressive diseases. size of the glycoproteins differs for each group of viruses. For
The spumaviruses, represented by a foamy virus, cause a

TABLE 54.1  Classification of Retroviruses

Subfamily Characteristics Examples
Oncovirinae Are associated with cancer and neurologic disorders —
Have eccentric nucleocapsid core in mature virion Mouse mammary tumor virus
B Have centrally located nucleocapsid core in mature virion Human T-cell lymphotropic virusa (HTLV-1, HTLV-2,
C
Have nucleocapsid core with cylindrical form HTLV-5), Rous sarcoma virus (chickens)
D Have slow onset of disease, cause neurologic disorders and immuno- Mason-Pfizer monkey virus
Lentivirinae Human immunodeficiency virusa (HIV-1, HIV-2), visna
suppression, are viruses with D-type cylindrical nucleocapsid core
Spumavirinae Cause no known clinical disease but cause characteristic vacuolated virus (sheep), caprine arthritis/encephalitis virus (goats)
Human foamy virusa
HERVs “foamy” cytopathology
Retrovirus sequences that are integrated into human genome Human placental virus

aAlso classified as complex retroviruses because of the requirement for accessory proteins for replication.
HERVs, Human endogenous retroviruses.

54  •  Retroviruses 535

A-type B-type BOX 54.1  Unique Characteristics of
Retroviruses
C-type D-type
Virus has an enveloped spherical virion that is 80 to 120 nm in
Fig. 54.1 1 Morphologic distinction of retrovirions. The morphology diameter and encloses a capsid containing two copies of the
and position of the nucleocapsid core are used to classify the viruses. positive-strand RNA genome (≈9 kilobases for HIV and human
A-type particles are immature intracytoplasmic forms that bud through T-cell lymphotropic virus).
the plasma membrane and mature into B-type, C-type, and D-type par-
ticles. RNA-dependent DNA polymerase (reverse transcriptase), two
copies of tRNA, protease, and integrase enzymes are carried in
the virion.

Virus receptor is the initial determinant of tissue tropism.
Replication proceeds through a DNA intermediate termed the

provirus.
The provirus integrates randomly into the host chromosome and

becomes a cellular gene.
Transcription of the genome is regulated by the interaction of

host transcription factors with promoter and enhancer ele-
ments in the long terminal repeat portion of the genome.
Simple retroviruses encode gag, pol, and env genes. Complex
viruses also encode accessory genes (e.g., tat, rev, nef, vif, and
vpu for HIV).
Virus assembles and buds from the plasma membrane.
Final morphogenesis of HIV requires protease cleavage of Gag and
Gag-Pol polypeptides after envelopment.

tRNA, Transfer RNA.

TM (gp41)
SU (gp120)

MA (p17)

CA (p24)

Core
Envelope

RNA

A tRNA

Reverse
transcriptase
(pol)
NC (p7 p9)

100 nm Fig. 54.3  Cross section of HIV. The enveloped virion contains two iden-
tical ribonucleic acid (RNA) strands, RNA polymerase, integrase, and
B two transfer RNAs (tRNA) base-paired to the genome within the pro-
tein core. This is surrounded by proteins and a lipid bilayer. The enve-
Fig. 54.2  Electron micrographs of two retroviruses. (A) HIV. Note the lope spikes are the glycoprotein (gp)120 attachment protein and gp41
cone-shaped nucleocapsid in several of the virions. (B) Human T-cell fusion protein. CA, Capsid; MA, matrix; NC, nucleocapsid; SU, surface
lymphotropic virus. Note the C-type morphology characterized by a component; TM, transmembrane component of envelope glycopro-
central symmetric nucleocapsid. (From Belshe, R.B., 1991. Textbook of tein. (Modified from Gallo, R.C., Montagnier, L., 1988. AIDS in 1988. Scien-
Human Virology, second ed. Mosby, St Louis, MO.) tific American 259, 41–48. Copyright George Kelvin.)

example, the (glycoprotein) gp62 of HTLV-1 is cleaved into
gp46 and p21, and the gp160 of HIV is cleaved into gp41 and
gp120. These glycoproteins form lollipop-like trimer spikes
that are visible on the surface of the virion. The larger of
the HIV glycoproteins (gp120), which binds to cell-surface

536 SECTION 5  •  Virology

rex TABLE 54.2  Retrovirus Genes and Their Function

LTR GAG POL LTR Gene Virus Function
pX gag All
ENV Group-specific antigen: core and capsid
int All proteins
tax pol All
1 2 3 4 5 6 7 8 9 kb Integrase
pro All
A env All Polymerase: reverse transcriptase, prote-
pX HTLV ase, integrase

5′ LTR GAG - POL ENV Protease
R pr rt su (gp120) tm (gp41) 3′ LTR
Envelope: glycoproteins
tat NEF R
Sequence containing tax, rex, p12, p13,
rev p30, and HBZ: facilitate persistent viral
U3 in VPR hbz HTLV infection of the host
U5 VIF
tax HTLV Regulator of tax, promotes cell prolifera-
VPU tat HIV-1 tion
U3 rex HTLV
U5 Transactivation of viral and cellular genes
ma ca nc rev HIV-1
GAG Transactivation of viral and cellular genes
nef HIV-1
1 2 3 4 5 6 7 8 9 kb Regulation of RNA splicing and promo-
vif HIV-1 tion of export to cytoplasm
B vpu HIV-1
vpr (vpxa) HIV-1 Regulation of RNA splicing and promo-
Fig. 54.4  Genomic structure of human retroviruses. (A) Human T-cell tion of export to cytoplasm
lymphotropic virus (HTLV-1). The pX gene includes sequences for tax,
rex, p12, p13, p30, and HBZ. (B) HIV-1. The genes are defined in Table Decreases cell-surface CD4; facilitates
54.2 and Fig. 54.3. Unlike the other genes of these viruses, production T-cell activation, progression to AIDS
of the messenger RNA for tax and rex genes (HTLV-1) and tat and rev (essential)
genes (HIV) requires excision of two intron units. HIV-2 has a similar
genome map but has a vpx but not a vpu gene. ENV, Envelope glyco- Virus infectivity, promotion of assembly,
protein gene; GAG, group antigen gene; LTR, long terminal repeat; POL, blocks a cellular antiviral protein
polymerase gene. Protein nomenclature for HIV: ca, Capsid protein; in,
integrase; ma, matrix protein; nc, nucleocapsid protein; pr, protease; rt, Facilitates virion assembly and release,
reverse transcriptase; su, surface glycoprotein component; tm, trans- induces degradation of CD4
membrane glycoprotein component. (Modified from Belshe, R.B., Text-
book of Human Virology, second ed. Mosby, St Louis, MO.) Transport of complementary DNA to
nucleus, arresting of cell growth; facili-
receptors, initially determines the tissue tropism of the virus LTR All tates replication in macrophages
and is recognized by neutralizing antibody. The smaller
subunit (gp41 in HIV) forms the lollipop stick and promotes Promoter, enhancer elements
cell-to-cell fusion. The gp120 of HIV is extensively glycosyl-
ated, and its antigenicity can drift and receptor specificity can aOnly in HIV-2.
shift by mutations that occur during the course of a chronic HIV HTLV, Human T-cell lymphotropic virus; LTR, long terminal repeat (sequence).
infection. These factors impede antibody clearance of the
virus.  envelope and cell plasma membrane close together, allow-
ing the gp41 to interact with and promote fusion of the two
Replication membranes. Binding to CCR5 and gp41-mediated fusion
are both targets for antiviral drugs. HIV can also bind to a
Replication of HIV will serve as an example for the other ret- cellular adhesion molecule, α-4 β-7 integrin (also known as
roviruses unless noted. Infection starts with binding of the VLA-4 [very late antigen-4] and the gut homing receptor
viral glycoprotein spikes (trimer of gp120 and gp41 mole- for T cells), and dendritic cell–specific intercellular adhesion
cules) to the primary receptor, the CD4 protein, and then molecule-3-grabbing nonintegrin (DC-SIGN) on dendritic
a second receptor, a 7-transmembrane G-protein–coupled and other cells.
chemokine receptor (Fig. 54.5). Binding to these receptors
is the initial and major determinant of tissue tropism and host Once the genome is released into the cytoplasm, the
range for a retrovirus. The co-receptor used on initial infec- early phase of replication begins. The RT, encoded by
tion by HIV is CCR5, which is expressed on myeloid and the pol gene, uses the tRNA in the virion as a primer and
peripheral, activated, central memory, intestinal, synthesizes a complementary negative-strand DNA
and other subsets of CD4 T cells (macrophages, [M]- (cDNA). The RT also acts as a ribonuclease H, degrades
tropic virus). Later, during chronic infection of a person, the RNA genome, and then synthesizes the positive strand
the env gene mutates so that the gp120 binds to a different of DNA (Fig. 54.7). The RT is the major target for antiviral
chemokine receptor (CXCR4), which is expressed primar- drugs. During the synthesis of the virion DNA (provirus),
ily on T cells (T-tropic virus) (Fig. 54.6). Binding to the sequences from each end of the genome (U3 and U5) are
chemokine receptor activates the cell and brings the viral duplicated, attaching the LTRs to both ends. This process
creates sequences necessary for integration and creates
enhancer and promoter sequences within the LTR for regula-
tion of transcription. The DNA copy of the genome is larger
than the original RNA.

54  •  Retroviruses 537

CD4

Proviral DNA Unintegrated Membrane Co- HIV gp41
linear cDNA receptor T cell
Reverse
transcriptase

Genomic gp120
RNA
Nucleus

Integrated CD4 Chemokine
proviral DNA receptor

5′ cap genomic RNA
5′ cap tat mRNA
5′ cap
5′ cap Rev mRNA
5′ cap ENV mRNA
gag pol
5′ cap gag

Genomic mRNA
RNA
Protein synthesis,
processing and assembly RNA

gp120/41 gp120 Chemokine
receptor
Budding

CD4

gp41

Maturation (protease action) T cell

Fig. 54.5 Life cycle of HIV. HIV binds to CD4 and chemokine co- Fig. 54.6  Target cell binding of human immunodeficiency virus (HIV).
receptors and enters by fusion. The genome is reverse transcribed The CCR5 chemokine receptor is a co-receptor with CD4 on initial infec-
into deoxyribonucleic acid (DNA) in the cytoplasm, enters the nucleus, tion of an individual, and after mutation of the env gene, the CXCR4
and is integrated into the nuclear DNA. Transcription and translation receptor is also used. RNA, Ribonucleic acid. (Modified from Balter, M.,
of the genome occur as a cellular gene in a fashion similar to that of 1988. New hope in HIV disease. Science 274, 1988.)
human T-cell lymphotropic virus (see Fig. 54.7). The virus assembles at
the plasma membrane and matures after budding from the cell. cDNA, nuclear pores of resting T cells. Dissolution of the nuclear
Complementary DNA; mRNA, messenger ribonucleic acid. (Modified envelope on cell division is required by other retroviruses.
from Fauci, A.S., 1988. The human immunodeficiency virus: infectivity and The cDNA is then spliced into the host chromosome with
mechanisms of pathogenesis. Science 239, 617–622.) the aid of a virus-encoded, virion-carried enzyme, inte-
grase. Integration requires cell growth, but the cDNA of
RT is very error prone. For example, the error rate for the HIV and other lentiviruses can remain in the nucleus and
RT from HIV is one error per 2000 bases, or approximately cytoplasm in a nonintegrated circular DNA form until the
five errors per genome (HIV, 9000 base pairs), which is the cell is activated. Integrase is a target for an antiviral drug.
equivalent of at least one typo on every page of this text
but different errors for every book. This genetic instability Once integrated, the late phase begins and viral DNA
of HIV is responsible for promoting the generation of new provirus is transcribed as a cellular gene by the host RNA
strains of virus during a person’s disease, which is a prop- polymerase II. Transcription of the genome produces a full-
erty that may alter the pathogenicity of the virus and pro- length RNA, which for simple retroviruses is processed to
mote antiviral resistance or immune escape. produce several mRNAs that contain the gag, gag-pol, or env
gene sequences. The full-length transcripts of the genome
Unlike other retroviruses, the double-stranded cDNA of can also be assembled into new virions.
HIV and other lentiviruses can enter the nucleus through
Because the provirus acts as a cellular gene, its replication
depends on the extent of methylation of the viral DNA and

538 SECTION 5  •  Virology

R U5 gag pol 1env pX U3 R Genomic
5′ CAP gag pol
AAAn 3′ RNA
U3 R U5
env pX U3 R U5 2 DNA

U3 R U5 gag pol env pX U3 R U5 3 Integrated

Cell DNA Cell DNA DNA
5′ CAP
R U5 gag pol 4env pX U3 R mRNA and

AAAn progeny virus

5′ LTR 3′ LTR
U3 R U5 U3 R U5

gag pol 5 Processing of
pr mRNA

env 6 Translation

Tax
Rex

p12

p30

Hbz

Fig. 54.7  Transcription and translation of human T-cell lymphotropic virus. (A similar but more complex approach is used for HIV.) (1) Genomic ribo-
nucleic acid (RNA) is reverse transcribed and (2) circularized and then (3) integrated into the host chromatin. (4) A full-length RNA and (5) individual
messenger RNAs (mRNAs) are processed from this RNA. The mRNA for tax, rex, and p30 require excision of two sequences from the gag-pol and env
sequences. The other mRNAs, including the env mRNA, require excision of one sequence. (6) Translation of these mRNAs produces polyproteins, which
are subsequently cleaved. AAAn, Polyadenylate. Gene nomenclature: env, Envelope glycoprotein; gag, group antigen gene; pr, protease; pol, poly-
merase; rex, regulator of splicing; tax, transactivator. Protein nomenclature: C, Carboxyl terminus of peptide; CA, capsid; MA, matrix; N, amino terminus;
NC, nucleocapsid; PR, protease; SU, surface component; TM, transmembrane component of envelope glycoprotein. Prefixes: gp, glycoprotein; gPr,
glycosylated precursor polyprotein; p, protein; PR, precursor polyprotein. (Adapted from Kannian, P., Green, P.L., 2010. Human T lymphotropic virus type 1
(HTLV-1): molecular biology and oncogenesis. Viruses 2 [9], 2037–2077.)

on the cell’s growth rate, but mostly on the ability of the of these genes promotes the growth of the infected T cell,
cell to recognize the enhancers and promoter sequences which enhances virus replication.
encoded in the LTR region. Stimulation of the cell by cyto-
kines or mitogens produced in response to other infections HIV replication is regulated by as many as six “acces-
generates transcription factors that bind to the LTR and for sory” gene products (see Table 54.2). The Tat protein,
HIV are required to activate transcription of the integrated like Tax, is a transactivator of the transcription of viral and
genome. For other retroviruses that encode viral onco- cellular genes. The Rev protein acts like the Rex protein
genes, these proteins promote cell growth and stimulate to regulate and promote transport of viral mRNA into the
transcription and hence viral replication. The ability of a cell cytoplasm. The Nef protein reduces cell-surface expression
to transcribe the retroviral genome is also a major determinant of CD4 and major histocompatibility complex I (MHC I) mol-
of tissue tropism and host range for a retrovirus. ecules, alters T-cell signaling pathways, regulates the cyto-
toxicity of the virus, and is required to maintain high viral
HTLV and HIV are complex retroviruses and undergo loads. The Nef protein appears to be essential for causing the
two phases of transcription. During the early phase, infection to progress to AIDS. The Vif protein promotes assem-
HTLV-1 expresses two proteins, Tax and Rex, which reg- bly and maturation and binds to an antiviral cellular protein
ulate viral replication. Unlike the other viral mRNAs, the (APOBEC-3G) to prevent it from hypermutating and inac-
mRNA for Tax and Rex requires more than one splicing tivating the cDNA and helps the virus replicate in myeloid
step. The rex gene encodes two proteins that bind to a struc- and other cells. The Vpu protein reduces cell-surface CD4
ture on the viral mRNA, preventing further splicing and expression and enhances virion release. The Vpr protein
promoting mRNA transport to the cytoplasm. The doubly (Vpx in HIV-2) is important for transport of the cDNA into
spliced tax/rex mRNA is expressed early (at a low concen- the nucleus. Vpr protein also arrests the cell in the G2 phase
tration of Rex), and structural proteins are expressed late of the growth cycle, which is likely to be optimal for HIV rep-
(at a high concentration of Rex). Late in the infection, Rex lication. Vpx facilitates virus replication in dendritic cells and
selectively enhances expression of the singly spliced struc- macrophages. Interestingly, this facilitates antigen presen-
tural genes, which are required in abundance. The tax protein tation on MHC-1 antigens, which promotes CD8 cytotoxic
is a transcriptional activator and enhances transcription T-cell production and can limit HIV-2 disease progression.
of the viral genome from the promoter gene sequence in the
5′ LTR. Tax also activates other genes, including those for The proteins translated from the gag, gag-pol, and env
interleukin (IL)-2, IL-3, granulocyte-macrophage colony- mRNAs are synthesized as polyproteins and are subse-
stimulating factor, and the receptor for IL-2. Activation quently cleaved to functional proteins (see Fig. 54.7).
The viral glycoproteins are synthesized, glycosylated, and

54  •  Retroviruses 539

Infection Mucosa Days
Colon-rectum DCs
Vagina Macrophages Weeks
CCR5-CD4 T cells
CNS
Lymph nodes mild disease

Acute HIV syndrome
Large viremia

Asymptomatic
steady level of HIV viremia

Persistent
lymphadenopathy

CXCR4-CD4 T cells targeted

Precipitous drop in Large viremia Drop in CD8 Years
CD4 T-cell numbers T-cell numbers

Severe immunodeficiency AIDS dementia
Opportunistic infections

Activation of latent viruses
Viral-related cancers

Fig. 54.8  Pathogenesis of human immunodeficiency virus (HIV). HIV causes lytic and latent infection of macrophage, dendritic cells, and CD4 T cells
and disrupts neuronal function. The outcomes of these actions are immunodeficiency and acquired immunodeficiency syndrome (AIDS) dementia.
CNS, Central nervous system. (Modified from Fauci, A.S., 1988. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science 239,
617–622.)

processed by the endoplasmic reticulum and Golgi appara- Human Immunodeficiency Virus
tus. These glycoproteins are then cleaved, associate to form
trimers, and migrate to the plasma membrane. There are four genotypes of HIV-1, designated M (main), N,
O, and P. Most HIV-1 is of the M subtype, and this is divided
The Gag and Gag-Pol polyproteins are acylated and into 11 subtypes, or clades, designated A to K (for HIV-2,
then bind to the plasma membrane containing the enve- A to F). The designations are based on differences in the
lope glycoprotein. The association of two copies of the sequence of their env (7% to 12% difference) and gag genes,
genome and cellular tRNA molecules promotes budding of and hence the antigenicity and immune recognition of the
the virion. gp120 and capsid proteins of these viruses.

Envelopment and release of retroviruses occur at the PATHOGENESIS AND IMMUNITY
cell surface. The HIV envelope picks up cellular proteins, The major determinant in the pathogenesis and disease
including MHC molecules, on budding. After envelop- caused by HIV is the virus tropism for CD4-express-
ment and release from the cell, the viral protease cleaves ing T cells and myeloid cells (Fig. 54.8 and Box 54.2).
the Gag and Gag-Pol polyproteins to release the RT and HIV-induced immunosuppression (AIDS) results from a
form the virion core, ensuring inclusion of these compo- reduction in the number of CD4 T cells, which decimates
nents into the virion. The protease step is required for the ability to activate and control innate and immune
the production of infectious virions and is a target for responses.
antiviral drugs.
During sexual transmission, HIV infects a mucosal sur-
Replication and budding of the retrovirus do not necessar- face, enters, and rapidly infects cells of the mucosa-associ-
ily kill the cell. HIV can also spread from cell to cell through ated lymphoid tissue (MALT), including the intestine. The
the production of multinucleated giant cells, or syncytia.
Syncytia are fragile, and their formation enhances the cyto-
lytic activity of the virus. 

540 SECTION 5  •  Virology

BOX 54.2  Disease Mechanisms of Human Stage 1 Stage 2 Stage 3
Immunodeficiency Virus
Acute Chronic Subclinical immune Skin Systemic
HIV primarily infects CD4 T cells and cells of the myeloid lineage infection lymphadenopathy immuno-
(e.g., monocytes, macrophages, alveolar macrophages of the dysfunction and deficiency
lung, dendritic cells, and microglial cells of the brain). Clinical latency
CD4 T-cell concentration (cells per cubic mm)1100 mucous
Virus mutates during chronic infection and switches from 1000
myeloid/T-cell tropic to T-cell tropic based on co-receptor membrane
preference. 900
immune
Virus causes lytic infection of activated permissive CD4 T cells and
induces apoptosis-like death of nonpermissive CD4 T cells. defects

Virus causes persistent low-level productive and latent infection 800 AIDS Viral load
of myeloid lineage cells and memory T cells.
700
Virus causes syncytia formation, with cells expressing large 600 AIDS dementia 107
amounts of CD4 antigen (T cells); subsequent lysis of the cells
occurs. 500 106
p24
Virus alters T-cell, dendritic cell, and macrophage cell function. 400 p24 105
Virus reduces CD4 T-cell numbers and helper-cell activation of
300
CD8 T-cell, macrophage, and other cell functions. 104
CD8 T-cell numbers and macrophage function decrease.
Infected microglial cells disrupt neuronal function. 200 R–5 virus X4 virus 103
100
initial stages of infection are mediated by M-tropic viruses
that bind to CD4 and the CCR5 chemokine receptors on 0 102
dendritic and other monocyte-macrophage lineage cells, 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84
as well as memory, TH1, most intestine-associated T cells, Time (months)
and other CD4 T cells. Individuals who are deficient in the
CCR5 receptor are also resistant to HIV infection, and CCR5 Virus
binding is a target for an antiviral drug. The CCR5-delta 32
mutation that prevents surface expression of this co-recep- CD4 and T-cell count
tor is prevalent in northern Europeans (1% are homozy-
gous and 10% to 15% are heterozygous for the mutation). Anti–HIV-1 antibody

Targeting of CCR5 or α-4 β-7 integrin–expressing CD4 T Fig. 54.9  Time course and stages of human immunodeficiency virus
cells rapidly depletes the intestinal lymphoid tissue of CD4 (HIV). A long clinical latency period follows the initial mononucleosis-
T cells. Depletion of the intestinal CD4 T-cell population like symptoms. Initial infection is with the R5–M-tropic virus, and fol-
wreaks havoc on immune regulation of normal gut flora lowing mutation, the X4–T-tropic virus. The progressive decrease
and maintenance of the intestinal mucosal epithelium, in the number of CD4 T cells, even during the latency period, allows
leading to leakage and diarrhea. opportunistic infections to occur. The stages in HIV disease are defined
by the CD4 T-cell levels and occurrence of opportunistic diseases. HIV
Macrophages, dendritic cells, memory T cells, and hema- can be detected by the presence of p24, HIV genome, or antibodies to
topoietic stem cells are persistently infected with HIV and the virus. (Modified from Redfield, R.R., Burke, D.S., 1996. HIV infection: the
are the major reservoirs and means of distribution of HIV clinical picture. Scientific American 259, 90–98; updated 1996.)
(Trojan horse). HIV can bind to the DC-SIGN lectin mole-
cule and remain on the surface of dendritic cells (including The course of HIV disease parallels the reduction in CD4 T-cell
follicular dendritic cells). CD4 T cells can be infected with numbers and the amount of virus in the blood (Fig. 54.9). HIV
the cell-bound HIV or by cell-to-cell transmission of virus infects and depletes the intestinal CCR5-expressing CD4 T
on binding to the dendritic cell. Late in the disease progres- cells very soon after infection. During the subsequent acute
sion, mutation in the env gene for the gp120 occurs for phase of the infection, there is a large burst of virus produc-
some of the virus, and this shifts its tropism from M-tropic tion (107 particles per milliliter of plasma). T-cell prolifera-
(R5) to T-tropic (X4 virus). The gp120 of the T-tropic tion in response to antigen presentation by infected dendritic
virus binds to CD4 and the CXCR4 chemokine receptor. cells, macrophages, and even activated CD4 T cells promotes
Some viruses may use both receptors (R5X4 viruses). This a mononucleosis-like syndrome. CD8 T cells kill many
expands the viral target range to include almost all CD4 T infected cells and limit virus production. Virus levels in the
cells. blood decrease and the individual is asymptomatic (latent
period), but viral replication continues in the lymph nodes,
Killing of CD4 T cells may result from direct HIV-induced causing disruption of their structure and function, and
cytolysis (including syncytia formation) and cytotoxic CD4 T-cell numbers continue to drop. Late in the disease,
T-cell–induced immune cytolysis, but large numbers of CD4 levels decrease to the point that they cannot maintain
nonpermissive resting T cells commit a type of inflamma- the antiviral action of CD8 T cells, and then virus levels in
tory cell suicide (pyroptosis) induced by the presence of the blood increase greatly, T-tropic virus rises, CD4 T-cell
large amounts of nonintegrated circular DNA copies of the numbers drop faster, the structures of the lymph nodes are
genome. Pyroptosis is an inflammatory form of cell death destroyed, and the patient becomes immunodeficient.
that may lure more unactivated T cells to the site to be
infected and also succumb to pyroptosis. The central role of the CD4 helper T cells in the initiation
and control of innate and immune responses is indicated by
the onset of opportunistic diseases after HIV infection (Fig.
54.10). Activated CD4 T cells initiate immune responses
by the release of cytokines required for the activation of
epithelial cells, neutrophils, macrophages, other T cells, B
cells, and natural killer cells. The CD4 TH17 responses that
activate neutrophils and protect the mucoepithelium are

54  •  Retroviruses 541

Growth and Activation of Control of bacteria,
control of innate epithelial cells, intracellular bacteria,
neutrophils, and
and immune macrophages and fungi
responses

Growth factors CD4 IL-17
and TGF-β T cell IFN-γ
IL-2
IL-4, IL-5, IL-10

Growth and Growth of NK, IFN-γ Control of viruses,
control of B cells CD4, and CD8 intracellular bacteria,
tumors, HIV progression
T cells

Fig. 54.10  CD4 T cells have a critical role in activating and regulating cell-mediated immune responses, especially toward intracellular pathogens.
Human immunodeficiency virus (HIV)–induced loss of CD4 T cells results in loss of the functions activated and regulated by the indicated cytokines. IFN,
Interferon; IL, interleukin; NK, natural killer; TGF-β, transforming growth factor-β.

the first to be depleted (CD4 numbers < 500/μL), increasing TABLE 54.3  Means of Human Immunodeficiency Virus
susceptibility to fungal and bacterial infections. As the CD4 Escape from the Immune System
T cells decrease (CD4 numbers < 200/μL), TH1 responses
dissipate and cannot activate sufficient numbers of CD8 T Characteristic Function
cells and macrophages to control new infections of intra-
cellular bacteria and latent viruses (e.g., herpesviruses and Infection of dendritic cells, Loss of cellular activators and con-
JC polyomavirus progressive multifocal leukoencepha- macrophages, and CD4 T trollers of the immune system
lopathy [PML] and Epstein-Barr virus [EBV] and human helper cells
herpes virus [HHV]-8–associated cancers [Hodgkin and Evasion of antibody detection
non-Hodgkin lymphomas, Kaposi sarcoma]). Antigenic drift (via mutation)
of gp120
In addition to immunodepression, HIV can also cause
neurologic abnormalities. The microglial cell and mac- Heavy glycosylation of gp120 Evasion of antibody detection
rophage are the predominant HIV-infected cell types in
the brain. Infected monocytes and microglial cells release Direct cell-to-cell spread and Evasion of antibody detection
neurotoxic substances or chemotactic factors that promote syncytia formation
inflammatory responses and neuronal death in the brain.
Immunosuppression also puts the individual at risk of EPIDEMIOLOGY
opportunistic infections of the brain. AIDS was first noted in homosexual men in the United
States but has spread in epidemic proportions through-
The innate and immune response attempts to restrict viral out the population (Figs. 54.11 and 54.12; Box 54.3).
infection but also contributes to pathogenesis. The infected Although the number of HIV-infected people is very large
cells have enzymes that restrict retrovirus replication (includ- and continues to rise, as of 2016, the rate of increase has
ing endogenous retroviruses), but HIV can override their begun to decrease because of prevention campaigns.
actions. The presence of unintegrated HIV cDNA triggers type
1 interferon production and inflammatory cell suicide (pyrop- HIV-1 is genetically most similar to a chimpanzee immu-
tosis). CD8 T cells are critical to limiting HIV disease progres- nodeficiency virus. HIV-2 is more similar to simian immu-
sion. CD8 T cells can kill infected cells by direct cytotoxic action nodeficiency virus. The initial human infection occurred in
and can produce suppressive factors that restrict viral replica- Africa before the 1930s but went unnoticed in rural areas.
tion, including chemokines that also block the binding of virus The migration of infected people to the cities and increased
to its co-receptor. Individuals with certain MHC types (human nonsterile use of syringes after the 1960s brought the virus
leukocyte antigen [HLA] B27 or B57) will preferentially bind into population centers, and cultural acceptance of prostitu-
HIV peptides rather than cellular peptides to make infected tion promoted its transmission throughout the population.
cells better targets for CD8 T-cell killing, and these individuals
are more resistant to HIV disease. Neutralizing antibodies are Geographic Distribution
generated against gp120. Antibody-coated virus can be infec- HIV-1 infections are spreading worldwide, with the largest
tious, however, and is taken up by macrophages. number of AIDS cases in sub-Saharan Africa, but with a
growing number of cases in Asia, the United States, and the
HIV has several ways of escaping immune control (Table rest of the world (see Fig. 54.12). HIV-2 is more prevalent in
54.3). Most significant is the virus’ ability to undergo muta- Africa (especially West Africa) than in the United States and
tion and hence alter its antigenicity and escape antibody other parts of the world. HIV-2 produces a disease similar to
clearance. Persistent infection of macrophages and resting but less severe than AIDS. Heterosexual transmission is the
CD4 T cells maintains the virus in an immune-privileged major means of spread of HIV-1 and HIV-2 in Africa, with
cell and cells in immune-privileged tissues (e.g., central ner- men and women equally affected by these viruses. The dif-
vous system and genital organs). Ultimately, infection of ferent clades of HIV-1 have different worldwide geographic
CD4 T cells compromises the entire immune system.  distributions.

542 SECTION 5  •  Virology Male-to-male sexual contact Although rare, there are cases of long-term survivors.
+ Injection drug use* Some of these result from infection with HIV strains that
lnjection drug use 3% (1,201) lack a functional Nef protein. The Nef protein is necessary
6% (2,224) to promote the progression of HIV infection to AIDS. Resis-
tance to the virus also correlates with a lack of or mutation
Heterosexual of the CCR5 chemokine co-receptor for the virus or specific
contact HLA types that promote more vigorous cytotoxic T-cell
responses that control the infection. 
24% (9,578) Transmission
The presence of HIV in the blood, semen, and vaginal
Male-to-male secretions of infected people and the long asymptomatic
sexual contact period of infection are factors that have promoted spread
67% (26,570) of the disease through sexual contact and exposure to con-
taminated blood and blood products (Table 54.4). The fetus
Fig. 54.11  Acquired immunodeficiency syndrome (AIDS) statistics for and newborn are likely to acquire the virus from an infected
the United States as of 2016. The percentages of AIDS cases are pre- mother. HIV is not, however, transmitted by casual contact,
sented by exposure category. In the United States, unlike Africa and touching, hugging, kissing, coughing, sneezing, insect bites,
many other parts of the world, men having sex with men (MSM) is water, food, utensils, toilets, swimming pools, or public baths. 
the largest exposure category. However, intravenous (IV) drug abus- Populations at Highest Risk
ers and heterosexual partners are becoming more prevalent. (Cen- Sexually active people (men who have sex with men [MSM]
ters for Disease Control and Prevention, 2016. HIV Surveillance Report. and heterosexual men and women), IV drug abusers and
https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv- their sexual partners, and the newborns of HIV-positive
info-sheet-diagnoses-of-HIV-infection-2016.pdf.) accessed 10.4.2019

Prevalence of HIV among adults aged 15 to 49, 2017
By WHO region

0 875 1,750 3,500 Kilometers

Prevalence (%) by WHO region Europe: 0.4 [0.4–0.4]
Americas: 0.5 [0.4–0.6]
Eastern Mediterranean: 0.1 [<0.1–0.1] Africa: 4.1 [3.4–4.8]
Western Pacific: 0.1 [<0.1–0.2]
South-East Asia: 0.3 [0.2–0.4]

Global prevalence: 0.8% [0.6–0.9]

Fig. 54.12  Upper estimates of numbers of people living with HIV infections as of the end of 2017. More than 70 million people have been infected with
the HIV virus, about 35 million people have died of HIV, and 36.9 million (31.1 to 43.9 million) people were living with HIV at the end of 2017.The high-
est rates are in sub-Saharan Africa. (Global Health Observatory Data, 2019. Summary of the global HIV epidemic [2018]. http://www.who.int/gho/hiv/en/
[accessed 13.09.2018.])

54  •  Retroviruses 543

BOX 54.3  Epidemiology of Human transmission. However, heterosexual transmission by vaginal
Immunodeficiency Virus Infections intercourse and IV drug abuse have become the major routes
by which HIV is being spread in the larger population. The
Disease Viral Factors prevalence of HIV in drug abusers stems from sharing contam-
inated syringe needles, which is a common practice in “shoot-
Enveloped virus is easily inactivated and must be transmitted in ing galleries.” In New York alone, more than 80% of IV drug
body fluids. abusers are positive for the HIV antibody, and these people are
now the major source of heterosexual and congenital trans-
Disease has a long prodromal period. mission of the virus. Tattoo needles and contaminated inks are
Virus can be shed before development of identifiable symptoms.  other potential means by which HIV can be transmitted.

Transmission Before 1985, people receiving blood transfusions or
organ transplants and hemophiliacs receiving clotting fac-
Virus is present in blood, semen, and vaginal secretions. tors from pooled blood were at high risk for HIV infection.
See Table 54.4 for modes of transmission.  HIV was spread in many countries by health care work-
ers using shared or improperly sterilized syringe needles
Who Is at Risk? or instruments. Proper screening of the blood supply and
transplant tissue in the United States and elsewhere has
Intravenous drug abusers, sexually active people with many practically eliminated the danger of HIV being transmit-
partners (MSM and heterosexual), prostitutes, newborns of HIV- ted in blood transfusions (see Fig. 54.11). Hemophiliacs
positive mothers, sexual partners of infected individuals. who receive pooled clotting factors are protected further by
proper handling of the factor (prolonged heating) to kill the
Blood and organ transplant recipients and hemophiliacs treated virus or by the use of genetically engineered proteins.
before 1985 (before prescreening programs). 
Health care workers are at risk for HIV infection from
Geography/Season accidental needlesticks or cuts, or through the exposure
of broken skin and mucosal membranes to contaminated
There is an expanding epidemic worldwide. blood. Fortunately, studies of needlestick victims have
There is no seasonal incidence.  shown that seroconversion occurs in less than 1% of those
exposed to HIV-positive blood. 
Modes of Control
CLINICAL SYNDROMES
Antiviral drugs limit progression of disease. AIDS is one of the most devastating epidemics ever recorded.
Antiviral drugs for pre- and post-exposure prophylaxis. Most HIV-infected people will become symptomatic, and the
No vaccines available. overwhelming majority of them will ultimately succumb to
Safe, monogamous sex helps limit spread. the disease without treatment. HIV disease progresses from
Sterile injection needles should be used. an asymptomatic nonspecific or mononucleosis-like dis-
Circumcision. ease to profound immunosuppression, referred to as AIDS
Large-scale screening programs of blood for transfusions, organs (Clinical Case 54.1; see Fig. 54.9). The diseases related to
AIDS mainly consist of opportunistic infections, cancers,
for transplants, and clotting factors used by hemophiliacs. and the direct effects of HIV on the central nervous system
(Table 54.5).
MSM, Men who have sex with men.
The initial symptoms after HIV infection (acute phase, 2
TABLE 54.4  Transmission of Human Immunodeficiency to 4 weeks after infection) may resemble those of influenza
Virus Infection or heterophile antibody negative mononucleosis, with
“aseptic” meningitis or a rash occurring up to 3 months
Routes Specific Transmission after infection (Box 54.4). As in EBV mononucleosis, the
symptoms stem from T-cell responses triggered by a wide-
KNOWN ROUTES OF TRANSMISSION spread infection of antigen-presenting cells (macrophages).
These symptoms subside spontaneously after 2 to 3 weeks
Inoculation in Transfusion of blood and blood products and are followed by a period of asymptomatic infection or a
blood persistent generalized lymphadenopathy that may last for
Needle sharing among intravenous drug several years. During this period, the virus is replicating in
abusers the lymph nodes.

Needlestick, open wound, and mucous mem- Deterioration of the immune response is indicated by
brane exposure in health care workers increased susceptibility to opportunistic pathogens. The
onset of symptoms correlates with a reduction in the num-
Tattoo needles ber of CD4 T cells to less than 500/μL and increased levels
of virus (as determined by genome quantitation techniques)
Sexual transmission Anal and vaginal intercourse and viral protein p24 in the blood. Full-blown AIDS occurs
when CD4 T-cell counts are less than 200/μL (often-
Perinatal Intrauterine transmission times to 50/μL or undetectable) and virus load is greater
transmission Peripartum transmission than 75,000 copies/mL and involves the onset of more
Breast milk

ROUTES NOT INVOLVED IN TRANSMISSION

Close personal Household members
contact Health care workers not exposed to blood

mothers are at highest risk for HIV infections, with black
and Hispanic persons disproportionately represented in the
HIV-positive population.

As already noted, AIDS was initially described in young,
promiscuous, homosexual men and is still prevalent in the
gay community. Anal intercourse is an efficient means of viral