Review of Medical Microbiology and Immunology, 13th Edition

37. DNA Enveloped Viruses

CHAPTER CONTENTS

HERPESVIRUSES

Herpes Simplex Viruses (HSV)

Varicella-Zoster Virus (VZV)

Cytomegalovirus (CMV)

Epstein–Barr Virus (EBV)

Human Herpesvirus 8 (Kaposi’s Sarcoma–Associated Herpesvirus)

POXVIRUSES

Smallpox Virus

Molluscum Contagiosum Virus

HEPADNAVIRUSES

Hepatitis B Virus

Self-Assessment Questions

Summaries Of Organisms

Practice Questions: USMLE & Course Examinations

HERPESVIRUSES

The herpesvirus family contains six important human pathogens: herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein–Barr virus, and human herpesvirus 8 (the cause of Kaposi’s sarcoma).

All herpesviruses are structurally similar. Each has an icosahedral core surrounded by a lipoprotein envelope (Figure 37–1). The genome is linear double-stranded DNA. The virion does not contain a polymerase. They are large (120–200 nm in diameter), second in size only to poxviruses.

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FIGURE 37–1 Herpes simplex virus (HSV)—electron micrograph. Three HSV virions are visible. Short arrow points to the envelope of an HSV virion. Long arrow points to the nucleocapsid of the virion. The dark area between the inner nucleocapsid and the outer envelope is the tegument. (Figure courtesy of Dr. John Hierholzer, Public Health Image Library, Centers for Disease Control and Prevention.)

They replicate in the nucleus, form intranuclear inclusions, and are the only viruses that obtain their envelope by budding from the nuclear membrane. The virions of herpesviruses possess a tegument located between the nucleocapsid and the envelope. This structure contains regulatory proteins, such as transcription and translation factors, which play a role in viral replication.

Herpesviruses are noted for their ability to cause latent infections. In these infections, the acute disease is followed by an asymptomatic period during which the virus remains in a quiescent (latent) state. When the patient is exposed to an inciting agent or immunosuppression occurs, reactivation of virus replication and disease can occur.1 With some herpesviruses (e.g., herpes simplex virus), the symptoms of the subsequent episodes are similar to those of the initial one; however, with others (e.g., varicella-zoster virus), they are different (Table 37–1).

TABLE 37–1 Important Features of Common Herpesvirus Infections

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Some information is available regarding the mechanism by which herpes simplex virus (HSV) and cytomegalovirus (CMV) initiate and maintain the latent state. Shortly after HSV infects neurons, a set of “latency-associated transcripts” (LATS) are synthesized. These noncoding, regulatory RNAs suppress viral replication. The precise mechanism by which they do so is unknown. The process by which latency is terminated and reactivation of viral replication occurs is unclear, but various triggers such as sunlight, fever, and stress are known. CMV establishes latency by producing microRNAs that inhibit the translation of mRNAs required for viral replication. Also, the CMV genome encodes a protein and an RNA that have the ability to inhibit apoptosis in infected cells. Inhibition of apoptosis allows the infected cell to survive.

Three of the herpesviruses, HSV types 1 and 2 and varicella-zoster virus (VZV), cause a vesicular rash, both in primary infections and in reactivations. Primary infections are usually more severe than reactivations. The other two herpesviruses, CMV and Epstein–Barr virus (EBV), do not cause a vesicular rash.

Four herpesviruses, namely HSV types 1 and 2, VZV, and CMV, induce the formation of multinucleated giant cells, which can be seen microscopically in the lesions. The importance of giant cells is best illustrated by the Tzanck smear, which reveals multinucleated giant cells in a smear taken from the painful vesicles of the genitals caused by HSV type 2 (Figure 37–2).

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FIGURE 37–2 Herpes simplex virus type 2—multinucleated giant cells in Tzanck smear. Arrow points to a multinucleated giant cell with approximately eight nuclei. (Figure courtesy of Dr. Joe Miller, Public Health Image Library, Centers for Disease Control and Prevention.)

The herpesvirus family can be subdivided into three categories based on the type of cell most often infected and the site of latency. The alpha herpesviruses, consisting of HSV types 1 and 2 and VZV, infect epithelial cells primarily and cause latent infection in neurons. The beta herpesviruses, consisting of CMVs and human herpesvirus 6, infect and become latent in a variety of tissues. The gamma herpesviruses, consisting of EBV and human herpesvirus 8 (HHV-8, Kaposi’s sarcoma–associated virus), infect and become latent primarily in lymphoid cells. Table 37–2 describes some important clinical features of the common herpesviruses.

TABLE 37–2 Clinical Features of Herpesviruses

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Certain herpesviruses are associated with or cause cancer in humans (e.g., Epstein–Barr virus is associated with Burkitt’s lymphoma and nasopharyngeal carcinoma, and human herpesvirus 8 causes Kaposi’s sarcoma). Several herpesviruses cause cancer in animals (e.g., leukemia in monkeys and lymphomatosis in chickens) (see Chapter 43).

HERPES SIMPLEX VIRUSES (HSV)

HSV type 1 (HSV-1) and type 2 (HSV-2) are distinguished by two main criteria: antigenicity and location of lesions. Lesions caused by HSV-1 are, in general, above the waist, whereas those caused by HSV-2 are below the waist. Table 37–3 describes some important differences between the diseases caused by HSV-1 and HSV-2.

TABLE 37–3 Comparison of Diseases Caused by HSV-1 and HSV-2

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Diseases

HSV-1 causes acute gingivostomatitis, recurrent herpes labialis (cold sores), keratoconjunctivitis (keratitis), and encephalitis, primarily in adults. HSV-2 causes herpes genitalis (genital herpes), neonatal encephalitis and other forms of neonatal herpes, and aseptic meningitis. Infection by HSV-1 or HSV-2 is a common cause of erythema multiforme.

Important Properties

HSV-1 and HSV-2 are structurally and morphologically indistinguishable. They can, however, be differentiated by the restriction endonuclease patterns of their genome DNA and by type-specific monoclonal antisera against glycoprotein G. Humans are the natural hosts of both HSV-1 and HSV-2.

Summary of Replicative Cycle

The cycle begins when HSV-1 binds first to heparan sulfate on the cell surface and then to a second receptor, nectin. Following fusion of the viral envelope with the cell membrane, the nucleocapsid and the tegument proteins are released into the cytoplasm. The viral nucleocapsid is transported to the nucleus, where it docks to a nuclear pore and the genome DNA enters the nucleus along with tegument protein VP16. The linear genome DNA now becomes circular. VP16 interacts with cellular transcription factors to activate transcription of viral immediate early (IE) genes by host cell RNA polymerase. IE mRNA is translated into IE proteins that regulate the synthesis of early proteins such as the DNA polymerase that replicates the genome and thymidine kinase. These two proteins are important because they are involved in the action of acyclovir, which is the most important drug effective against HSV.

Note that early protein synthesis by HSV can be subdivided into two categories: immediate early and early. Immediate early proteins are those whose mRNA synthesis is activated by a protein brought in by the incoming parental virion (i.e., no new viral protein synthesis is required for the production of the five immediate early proteins). The early proteins, on the other hand, do require the synthesis of new viral regulatory proteins to activate the transcription of their mRNAs.

The viral DNA polymerase replicates the genome DNA, at which time early protein synthesis is shut off and late protein synthesis begins. These late, structural proteins are transported to the nucleus, where virion assembly occurs. The virion obtains its envelope by budding through the nuclear membrane and exits the cell via tubules or vacuoles that communicate with the exterior.

In latently infected cells, such as HSV-infected neurons, circular HSV DNA resides in the nucleus and is not integrated into cellular DNA. Transcription of HSV DNA is limited to a few latency-associated transcripts (LATS). These noncoding, regulatory RNAs suppress viral replication. Reactivation of viral replication can occur at a later time when the genes encoding LATS are excised.

Transmission & Epidemiology

HSV-1 is transmitted primarily in saliva, whereas HSV-2 is transmitted by sexual contact. As a result, HSV-1 infections occur mainly on the face, whereas HSV-2 lesions occur in the genital area. However, oral–genital sexual practices can result in HSV-1 infections of the genitals and HSV-2 lesions in the oral cavity (this occurs in about 10%–20% of cases). Although transmission occurs most often when active lesions are present, asymptomatic shedding of both HSV-1 and HSV-2 does occur and plays an important role in transmission.

The number of HSV-2 infections has markedly increased in recent years, whereas that of HSV-1 infections has not. Roughly 80% of people in the United States are infected with HSV-1, and 40% have recurrent herpes labialis. Most primary infections by HSV-1 occur in childhood, as evidenced by the early appearance of antibody. In contrast, antibody to HSV-2 does not appear until the age of sexual activity.

Pathogenesis & Immunity

The virus replicates in the skin or mucous membrane at the initial site of infection, and then migrates up the neuron by retrograde axonal flow and becomes latent in the sensory ganglion cells. In general, HSV-1 becomes latent in the trigeminal ganglia, whereas HSV-2 becomes latent in the lumbar and sacral ganglia. During latency, most—if not all—viral DNA is located in the cytoplasm rather than integrated into nuclear DNA. The virus can be reactivated from the latent state by a variety of inducers (e.g., sunlight, hormonal changes, trauma, stress, and fever), at which time it migrates down the neuron and replicates in the skin, causing lesions.

The typical skin lesion is a vesicle that contains serous fluid filled with virus particles and cell debris. When the vesicle ruptures, virus is liberated and can be transmitted to other individuals. Multinucleated giant cells are typically found at the base of herpesvirus lesions.

Immunity is type-specific, but some cross-protection exists. However, immunity is incomplete, and both reinfection and reactivation occur in the presence of circulating IgG. Cell-mediated immunity is important in limiting herpesviruses, because its suppression often results in reactivation, spread, and severe disease.

Clinical Findings

HSV-1 causes several forms of primary and recurrent disease:

(1) Gingivostomatitis occurs primarily in children and is characterized by fever, irritability, and vesicular lesions in the mouth. The primary disease is more severe and lasts longer than recurrences. The lesions heal spontaneously in 2 to 3 weeks. Many children have asymptomatic primary infections.

(2) Herpes labialis (fever blisters or cold sores) is the milder, recurrent form and is characterized by crops of vesicles, usually at the mucocutaneous junction of the lips or nose (Figure 37–3). Recurrences frequently reappear at the same site.

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FIGURE 37–3 Herpes labialis—note vesicles on upper lip adjacent to the vermillion border of the lip caused by herpes simplex virus type 1. (Figure courtesy of Jack Resneck, Sr., MD.)

(3) Keratoconjunctivitis is characterized by corneal ulcers and lesions of the conjunctival epithelium. Recurrences can lead to scarring and blindness.

(4) Encephalitis caused by HSV-1 is characterized by a necrotic lesion in one temporal lobe. Fever, headache, vomiting, seizures, and altered mental status are typical clinical features. The onset may be acute or protracted over several days. The disease occurs as a result of either a primary infection or a recurrence. Magnetic resonance imaging often reveals the lesion. Examination of the spinal fluid typically shows a moderate increase of lymphocytes, a moderate elevation in the amount of protein, and a normal amount of glucose. HSV-1 encephalitis has a high mortality rate and causes severe neurologic sequelae in those who survive.

(5) Herpetic whitlow is a pustular lesion of the skin of the finger or hand. It can occur in medical personnel as a result of contact with patient’s lesions.

(6) Herpes gladiatorum, as the name implies, occurs in wrestlers and others who have close body contact. It is caused primarily by HSV-1 and is characterized by vesicular lesions on the head, neck, and trunk.

(7) Eczema herpeticum (Kaposi’s varicelliform eruption) is an infection of the skin of a patient with atopic dermatitis. Vesicular lesions are seen at the site of the atopic dermatitis (eczema). Most cases occur in children.

(8) Disseminated infections, such as esophagitis and pneumonia, occur in immunocompromised patients with depressed T-cell function.

HSV-2 causes several diseases, both primary and recurrent:

(1) Genital herpes is characterized by painful vesicular lesions of the male and female genitals and anal area (Figure 37–4). The lesions are more severe and protracted in primary disease than in recurrences. Primary infections are associated with fever and inguinal adenopathy. Asymptomatic infections occur in both men (in the prostate or urethra) and women (in the cervix) and can be a source of infection of other individuals. Many infections are asymptomatic (i.e., many people have antibody to HSV-2 but have no history of disease).

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FIGURE 37–4 Herpes genitalis—note vesicles on shaft of penis caused by herpes simplex virus type 2. (Figure courtesy of Jack Resneck, Sr., MD.)

Approximately 80% to 90% of herpes genitalis cases are caused by HSV-2. The remainder are caused by HSV-1 as a result of oral–genital contact. The clinical importance of this is that suppressive chemoprophylaxis for HSV-2 lesions should be considered because lesions caused by HSV-2 are more likely to recur than lesions caused by HSV-1.

(2) Neonatal herpes originates chiefly from contact with vesicular lesions within the birth canal. In some cases, although there are no visible lesions, HSV-2 is shed into the birth canal (asymptomatic shedding) and can infect the child during birth. Neonatal herpes varies from severe disease (e.g., disseminated lesions or encephalitis) to milder local lesions (skin, eye, mouth) to asymptomatic infection. Neonatal disease may be prevented by performing cesarean section on women with either active lesions or positive viral cultures. Both HSV-1 and HSV-2 can cause severe neonatal infections that are acquired after birth from carriers handling the child. Despite their association with neonatal infections, neither HSV-1 nor HSV-2 causes congenital abnormalities to any significant degree.

Serious neonatal infection is more likely to occur when the mother is experiencing a primary herpes infection than a recurrent infection for two reasons: (1) the amount of virus produced during a primary infection is greater than during a secondary infection, and (2) mothers who have been previously infected can pass IgG across the placenta, which can protect the neonate from serious disseminated infection.

(3) Aseptic meningitis caused by HSV-2 is usually a mild, self-limited disease with few sequelae.

Both HSV-1 and HSV-2 infections are associated with erythema multiforme. The rash of erythema multiforme appears as a central red area surrounded by a ring of normal skin outside of which is a red ring (“target” or “bull’s eye” lesion). The lesions are typically macular or papular and occur symmetrically on the trunk, hands, and feet. The rash is thought to be an immune-mediated reaction to the presence of HSV antigens. Acyclovir is useful in preventing recurrent episodes of erythema multiforme, probably by reducing the amount of HSV antigens. Many drugs, especially sulfonamides among the antimicrobial drugs, commonly cause erythema multiforme. Other prominent infectious causes include Mycoplasma pneumoniae and viruses such as hepatitis B virus and hepatitis C virus.

Erythema multiforme major, also known as Stevens-Johnson syndrome, is characterized by fever, erosive oral lesions, and extensive desquamating skin lesions. M. pneumoniae infection is the most common infectious cause of Stevens-Johnson syndrome.

Laboratory Diagnosis

An important diagnostic procedure is isolation of the virus from the lesion by growth in cell culture. The typical cytopathic effect occurs in 1 to 3 days, after which the virus is identified by fluorescent antibody staining of the infected cells or by detecting virus-specific glycoproteins in enzyme-linked immunosorbent assays (ELISAs). HSV-1 can be distinguished from HSV-2 by using monoclonal antibody against glycoprotein G often in an ELISA test.

A rapid presumptive diagnosis can be made from skin lesions by using the Tzanck smear, in which cells from the base of the vesicle are stained with Giemsa stain. The presence of multinucleated giant cells suggests herpesvirus infection (Figure 37–2).

If herpes encephalitis is suspected, a rapid diagnosis can be made by detecting HSV DNA in the spinal fluid by using a polymerase chain reaction (PCR) assay. The PCR assay is more sensitive than viral culture. The diagnosis of neonatal herpes infection typically involves the use of viral cultures or PCR assay.

Serologic tests such as the neutralization test can be used in the diagnosis of primary infections because a significant rise in antibody titer is readily observed. However, they are of no use in the diagnosis of recurrent infections because many adults already have circulating antibodies, and recurrences rarely cause a rise in antibody titer.

Treatment

Acyclovir (acycloguanosine, Zovirax) is the treatment of choice for encephalitis and systemic disease caused by HSV-1. It is also useful for the treatment of primary and recurrent genital herpes; it shortens the duration of the lesions and reduces the extent of shedding of the virus but does not cure the latent state. Acyclovir is also used to treat neonatal infections caused by HSV-2. Mutants of HSV-1 resistant to acyclovir have been isolated from patients; foscarnet can be used in these cases.

For HSV-1 eye infections, other nucleoside analogues (e.g., trifluridine [Viroptic]) are used topically. Oral acyclovir is also used for HSV keratitis. Penciclovir (a derivative of acyclovir) or docosanol (a long-chain saturated alcohol) can be used to treat recurrences of orolabial HSV-1 infections in immunocompetent adults. Valacyclovir (Valtrex) and famciclovir (Famvir) are used in the treatment of genital herpes and in the suppression of recurrences.

Note that no drug treatment of the primary infection prevents recurrences; drugs have no effect on the latent state, but prophylactic, long-term administration of acyclovir, valacyclovir, or famciclovir can suppress clinical recurrences.

Prevention

Valacyclovir (Valtrex) and famciclovir (Famvir) are used in the suppression of recurrent lesions, especially in those with frequent recurrences caused by HSV-2. Suppressive chemoprophylaxis also reduces shedding of the virus and, as a result, transmission to others. Prevention also involves avoiding contact with the vesicular lesion or ulcer. Cesarean section is recommended for women who are at term and who have genital lesions or positive viral cultures. Circumcision reduces the risk of infection by HSV-2. There is no vaccine against HSV-1 or HSV-2.

VARICELLA-ZOSTER VIRUS (VZV)

Disease

Varicella (chickenpox) is the primary disease; zoster (shingles) is the recurrent form.

Important Properties

VZV is structurally and morphologically similar to other herpesviruses but is antigenically different. It has a single serotype. The same virus causes both varicella and zoster. Humans are the natural hosts.

Summary of Replicative Cycle

The cycle is similar to that of HSV (see page 284).

Transmission & Epidemiology

The virus is transmitted by respiratory droplets and by direct contact with the lesions. Varicella is a highly contagious disease of childhood; more than 90% of people in the United States have antibody by age 10 years. Varicella occurs worldwide. Prior to 2001, there were more cases of chickenpox than any other notifiable disease, but the widespread use of the vaccine has significantly reduced the number of cases.

There is infectious VZV in zoster vesicles. This virus can be transmitted, usually by direct contact, to children and can cause varicella. The appearance of either varicella or zoster in a hospital is a major infection control problem because the virus can be transmitted to immunocompromised patients and cause life-threatening disseminated infection.

Pathogenesis & Immunity

VZV infects the mucosa of the upper respiratory tract, and then spreads via the blood to the skin, where the typical vesicular rash occurs. Multinucleated giant cells with intranuclear inclusions are seen in the base of the lesions. The virus infects sensory neurons and is carried by retrograde axonal flow into the cells of the dorsal root ganglia, where the virus becomes latent.

In latently infected cells, VZV DNA is located in the nucleus and is not integrated into cellular DNA. Later in life, frequently at times of reduced cell-mediated immunity or local trauma, the virus is activated and causes the vesicular skin lesions and nerve pain of zoster.

Immunity following varicella is lifelong: A person gets varicella only once, but zoster can occur despite this immunity to varicella. Zoster usually occurs only once. The frequency of zoster increases with advancing age, perhaps as a consequence of waning immunity.

Clinical Findings

Varicella

After an incubation period of 14 to 21 days, brief prodromal symptoms of fever and malaise occur. A papulovesicular rash then appears in crops on the trunk and spreads to the head and extremities (Figure 37–5). The rash evolves from papules to vesicles, pustules, and, finally, crusts. Itching (pruritus) is a prominent symptom, especially when vesicles are present. Varicella is mild in children but more severe in adults. Varicella pneumonia and encephalitis are the major rare complications, occurring more often in adults. Reyes syndrome, characterized by encephalopathy and liver degeneration, is associated with VZV and influenza B virus infection, especially in children given aspirin. Its pathogenesis is unknown.

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FIGURE 37–5 Varicella (chickenpox)—note vesicles on an erythematous base caused by varicella-zoster virus. (Figure courtesy of Richard P. Usatine, MD, and The Color Atlas of Family Medicine.)

Zoster

The occurrence of painful vesicles along the course of a sensory nerve of the head or trunk is the usual picture (Figure 37–6). The pain can last for weeks, and postzoster neuralgia (also known as postherpetic neuralgia) can be debilitating. In immunocompromised patients, life-threatening disseminated infections such as pneumonia can occur.

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FIGURE 37–6 Zoster (shingles)—note vesicles along the dermatome of a thoracic nerve caused by varicella-zoster virus. (Figure courtesy of Richard P. Usatine, MD, and The Color Atlas of Family Medicine.)

Laboratory Diagnosis

Although most diagnoses are made clinically, laboratory tests are available. A presumptive diagnosis can be made by using the Tzanck smear. Multinucleated giant cells are seen in VZV as well as HSV lesions (Figure 37–2). The definitive diagnosis is made by isolation of the virus in cell culture and identification with specific antiserum. A rise in antibody titer can be used to diagnose varicella but is less useful in the diagnosis of zoster.

Treatment

No antiviral therapy is necessary for chickenpox or zoster in immunocompetent children. Immunocompetent adults with either moderate or severe cases of chickenpox or zoster often are treated with acyclovir because it can reduce the duration and severity of symptoms. Immunocompromised children and adults with chickenpox, zoster, or disseminated disease should be treated with acyclovir. Disease caused by acyclovir-resistant strains of VZV can be treated with foscarnet. Two drugs similar to acyclovir, famciclovir (Famvir) and valacyclovir (Valtrex), can be used in patients with zoster to accelerate healing of the lesions, but none of these drugs can cure the latent state. There is some evidence that these drugs reduce the incidence of postzoster neuralgia.

Prevention

There are two vaccines against VZV: one designed to prevent varicella, called Varivax, and the other designed to prevent zoster, called Zostavax. Both contain live, attenuated VZV, but the zoster vaccine contains 14 times more virus than the varicella vaccine. The zoster vaccine is effective in preventing the symptoms of zoster, but does not eradicate the latent state of VZV.

The varicella vaccine is recommended for children between the ages of 1 and 12 years, whereas the zoster vaccine is recommended for people older than 60 years and who have had varicella. The varicella vaccine is given in two doses, whereas the zoster vaccine is given in one dose. Because these vaccines contain live virus, they should not be given to immunocompromised people or pregnant women.

Acyclovir is useful in preventing varicella and disseminated zoster in immunocompromised people exposed to the virus. Varicella-zoster immune globulin (VZIG), which contains a high titer of antibody to the virus, is also used for such prophylaxis.

CYTOMEGALOVIRUS (CMV)

Diseases

CMV causes cytomegalic inclusion disease (especially congenital abnormalities) in neonates. It is the most common cause of congenital abnormalities in the United States. CMV is a very important cause of pneumonia and other diseases in immunocompromised patients such as recipients of bone marrow and solid organ transplants. It also causes heterophil-negative mononucleosis in immunocompetent individuals.

Important Properties

CMV is structurally and morphologically similar to other herpesviruses but is antigenically different. It has a single serotype. Humans are the natural hosts; animal CMV strains do not infect humans. Giant cells are formed, hence the name cytomegalo.

Summary of Replicative Cycle

The cycle is similar to that of HSV (see page 284). One unique feature of CMV replication is that some of its “immediate early proteins” are translated from mRNAs brought into the infected cell by the parental virion rather than being translated from mRNAs synthesized in the newly infected cell.

Transmission & Epidemiology

CMV is transmitted by a variety of modes. Early in life, it is transmitted across the placenta, within the birth canal, and quite commonly in breast milk. In young children, its most common mode of transmission is via saliva. Later in life it is transmitted sexually; it is present in both semen and cervical secretions. It can also be transmitted during blood transfusions and organ transplants. CMV infection occurs worldwide, and more than 80% of adults have antibody against this virus.

Pathogenesis & Immunity

Infection of the fetus can cause cytomegalic inclusion disease, characterized by multinucleated giant cells with prominent intranuclear inclusions. Many organs are affected, and widespread congenital abnormalities result. Infection of the fetus occurs mainly when a primary infection occurs in the pregnant woman (i.e., when she has no antibodies that will neutralize the virus before it can infect the fetus). The fetus usually will not be infected if the pregnant woman has antibodies against the virus. Congenital abnormalities are more common when a fetus is infected during the first trimester than later in gestation, because the first trimester is when development of organs occurs and the death of any precursor cells can result in congenital defects.

Infections of children and adults are usually asymptomatic, except in immunocompromised individuals. CMV enters a latent state primarily in monocytes and can be reactivated when cell-mediated immunity is decreased. CMV can also persist in kidneys for years. Reactivation of CMV from the latent state in cervical cells can result in infection of the newborn during passage through the birth canal.

CMV has a specific mechanism of “immune evasion” that allows it to maintain the latent state for long periods. In CMV-infected cells, assembly of the major histocompatibility complex (MHC) class I–viral peptide complex is unstable, so viral antigens are not displayed on the cell surface and killing by cytotoxic T cells does not occur. In addition, CMV encodes several microRNAs, one of which binds to and prevents the translation of the cell’s mRNA for the class I MHC protein. This prevents viral proteins from being displayed on the infected cell surface, and killing by cytotoxic T cells does not occur.

CMV infection causes an immunosuppressive effect by inhibiting T cells. Host defenses against CMV infection include both circulating antibody and cell-mediated immunity. Cellular immunity is more important, because its suppression can lead to systemic disease.

Clinical Findings

Approximately 20% of infants infected with CMV during gestation show clinically apparent manifestations of cytomegalic inclusion disease such as microcephaly, seizures, deafness, jaundice, and purpura. The purpuric lesions resemble a “blueberry muffin” and are due to thrombocytopenia. Hepatosplenomegaly is very common. Cytomegalic inclusion disease is one of the leading causes of mental retardation in the United States. Infected infants can continue to excrete CMV, especially in the urine, for several years.

In immunocompetent adults, CMV can cause heterophil-negative mononucleosis, which is characterized by fever, lethargy, and the presence of abnormal lymphocytes in peripheral blood smears. Systemic CMV infections, especially pneumonitis, esophagitis, and hepatitis, occur in a high proportion of immunosuppressed individuals (e.g., those with renal and bone marrow transplants). In patients with acquired immunodeficiency syndrome (AIDS), CMV commonly infects the intestinal tract and causes intractable colitis with diarrhea. CMV also causes retinitis in AIDS patients, which can lead to blindness.

Laboratory Diagnosis

The preferred approach involves culturing in special tubes called shell vials coupled with the use of immunofluorescent antibody, which can make a diagnosis in 72 hours. The virus obtained in the culture can then be used to determine the drug susceptibility to ganciclovir.

Other diagnostic methods include fluorescent antibody and histologic staining of inclusion bodies in giant cells in urine and in tissue. The inclusion bodies are intranuclear and have an oval owls eye shape (Figure 37–7). A fourfold or greater rise in antibody titer is also diagnostic. PCR-based assays for CMV DNA or RNA in tissue or body fluids, such as spinal fluid and amniotic fluid, are also very useful.

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FIGURE 37–7 Cytomegalovirus—owl’s eye inclusion body. Arrow points to an “owl’s eye” inclusion body in the nucleus of an infected cell. (Figure courtesy of Dr. Edwin Ewing, Jr., Public Health Image Library, Centers for Disease Control and Prevention.)

CMV antigenemia can be measured by detecting pp65 within blood leukocytes using an immunofluorescence assay. pp65 is a protein located in the nucleocapsid of CMV and can be identified within infected leukocytes using fluorescein-labeled monoclonal antibody specific for pp65.

Treatment

Ganciclovir (Cytovene) is moderately effective in the treatment of CMV retinitis and pneumonia in patients with AIDS. Valganciclovir, which can be taken orally, is also effective against CMV retinitis. CMV strains resistant to ganciclovir and valganciclovir have emerged, mostly due to mutations in the d gene that encodes the phosphokinase. Drug susceptibility testing can be done.

Foscarnet (Foscavir) is also effective but causes more side effects. Unlike HSV and VZV, CMV is largely resistant to acyclovir. Cidofovir (Vistide) is also useful in the treatment of CMV retinitis. Fomivirsen (Vitravene) is an antisense DNA approved for the intraocular treatment of CMV retinitis. It is the first and, at present, the only antisense molecule to be approved for the treatment of human disease.

Prevention

There is no vaccine. Ganciclovir can suppress progressive retinitis in AIDS patients. Infants with cytomegalic inclusion disease who are shedding virus in their urine should be kept isolated from other infants. Blood for transfusion to newborns should be CMV antibody-negative. If possible, only organs from CMV antibody-negative donors should be transplanted to antibody-negative recipients. A high-titer immune globulin preparation (CytoGam) is used to prevent disseminated CMV infections in organ transplant patients.

EPSTEIN–BARR VIRUS (EBV)

Diseases

EBV causes infectious mononucleosis. It is associated with Burkitt’s lymphoma, other B-cell lymphomas, and nasopharyngeal carcinoma. EBV also causes hairy leukoplakia.

Important Properties

EBV is structurally and morphologically similar to other herpesviruses but is antigenically different. The most important antigen is the viral capsid antigen (VCA), because it is used most often in diagnostic tests. The early antigens (EA), which are produced prior to viral DNA synthesis, and Epstein–Barr nuclear antigen (EBNA), which is located in the nucleus bound to chromosomes, are sometimes diagnostically helpful as well. Two other antigens, lymphocyte-determined membrane antigen and viral membrane antigen, have been detected also. Neutralizing activity is directed against the viral membrane antigen.

Humans are the natural hosts. EBV infects mainly lymphoid cells, primarily B lymphocytes. EBV also infects the epithelial cells of the pharynx, resulting in the prominent sore throat. In latently infected cells, EBV DNA is in the nucleus and is not integrated into cellular DNA. Some, but not all, genes are transcribed, and only a subset of those are translated into protein.

Summary of Replicative Cycle

The cycle is similar to that of HSV (see page 284). EBV enters B lymphocytes at the site of the receptor for the C3 component of complement.

Transmission & Epidemiology

EBV is transmitted primarily by the exchange of saliva (e.g., during kissing). The saliva of people with a reactivation of a latent infection as well as people with an active infection can serve as a source of the virus. In contrast to CMV, blood transmission of EBV is very rare.

EBV infection is one of the most common infections worldwide; more than 90% of adults in the United States have antibody. Infection in the first few years of life is usually asymptomatic. Early infection tends to occur in individuals in lower socioeconomic groups. The frequency of clinically apparent infectious mononucleosis, however, is highest in those who are exposed to the virus later in life (e.g., college students).

Pathogenesis & Immunity

The infection first occurs in the oropharynx and then spreads to the blood, where it infects B lymphocytes. Cytotoxic T lymphocytes react against the infected B cells. The T cells are the “atypical lymphs” seen in the blood smear. EBV remains latent within B lymphocytes.

The immune response to EBV infection consists first of IgM antibody to the VCA. IgG antibody to the VCA follows and persists for life. The IgM response is therefore useful for diagnosing acute infection, whereas the IgG response is best for revealing prior infection. Lifetime immunity against second episodes of infectious mononucleosis is based on antibody to the viral membrane antigen.

In addition to the EBV-specific antibodies, nonspecific heterophil antibodies are found. The term heterophil refers to antibodies that are detected by tests using antigens different from the antigens that induced them. The heterophil antibodies formed in infectious mononucleosis agglutinate sheep or horse red blood cells in the laboratory. (Cross-reacting Forssman antibodies in human serum are removed by adsorption with guinea pig kidney extract prior to agglutination.) Note that these antibodies do not react with any component of EBV. It seems likely that EBV infection modifies a cell membrane constituent such that it becomes antigenic and induces the heterophil antibody. Heterophil antibodies usually disappear within 6 months after recovery. These antibodies are not specific for EBV infection and are also seen in individuals with hepatitis B and serum sickness.

Clinical Findings

Infectious mononucleosis is characterized primarily by fever, sore throat, lymphadenopathy, and splenomegaly. Anorexia and lethargy are prominent. Hepatitis is frequent; encephalitis occurs in some patients. Spontaneous recovery usually occurs in 2 to 3 weeks. Splenic rupture, associated with contact sports such as football, is a feared but rare complication of the splenomegaly.

In addition to the common form of infectious mononucleosis described in the previous paragraph, EBV causes a severe, often fatal, progressive form of infectious mononucleosis that occurs in children with an inherited immunodeficiency called X-linked lymphoproliferative syndrome. The mutated gene encodes a signal transduction protein required for both T-cell and natural killer–cell function. The mortality rate is 75% by age 10. Bone marrow or cord blood transplants may cure the underlying immunodeficiency. EBV also causes hairy leukoplakia—a whitish, nonmalignant lesion with an irregular “hairy” surface on the lateral side of the tongue (Figure 37–8). It occurs in immunocompromised individuals, especially AIDS patients.

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FIGURE 37–8 Hairy leukoplakia—note whitish plaques on lateral aspect of tongue caused by Epstein–Barr virus. (Reproduced with permission from Wolff K, Johnson R. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill, 2009. Copyright © 2009 by The McGraw-Hill Companies, Inc.)

EBV infection is associated with several cancers, namely Burkitt’s lymphoma, some forms of Hodgkin’s lymphoma, and nasopharyngeal carcinoma. The word associated refers to the observation that EBV infection is the initiating event that causes the cells to divide, but that event itself does not cause a malignancy. It requires additional steps for malignant transformation to occur. Reduced cell-mediated immunity predisposes to the uncontrolled growth of the EBV-infected cells.

Another EBV-associated disease is post-transplant lymphoproliferative disorder (PTLD). The most common form of PTLD is a B-cell lymphoma. PTLD occurs following both bone marrow transplants and solid organ transplants. The main predisposing factor to PTLD is the immunosuppression required to prevent rejection of the graft. The lymphoma will regress if the degree of immunosuppression is reduced.

Laboratory Diagnosis

The diagnosis of infectious mononucleosis in the clinical laboratory is based primarily on two approaches:

(1) In the hematologic approach, absolute lymphocytosis occurs, and as many as 30% abnormal lymphocytes are seen on a smear. These atypical lymphs are enlarged, have an expanded nucleus, and an abundant, often vacuolated cytoplasm (Figure 37–9). They are cytotoxic T cells that are reacting against the EBV-infected B cells.

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FIGURE 37–9 Atypical lymphocytes in infectious mononucleosis—note two atypical lymphocytes, each with an enlarged nucleus and abundant cytoplasm on the left side. The lymphocyte on the right side appears normal. (Reproduced with permission from Fauci AS, Braunwald E, Kasper DL et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill, 2008, pg 1107. Copyright © 2008 by The McGraw-Hill Companies, Inc.)

(2) In the immunologic approach, there are two types of serologic tests: (a) The heterophil antibody test is useful for the early diagnosis of infectious mononucleosis because it is usually positive by week 2 of illness. However, because the antibody titer declines after recovery, it is not useful for detection of prior infection. The Monospot test is often used to detect the heterophil antibody; it is more sensitive, more specific, and less expensive than the tube agglutination test. (b) The EBV-specific antibody tests are used primarily in diagnostically difficult cases. The IgM VCA antibody response can be used to detect early illness; the IgG VCA antibody response can be used to detect prior infection. In certain instances, antibodies to EA and EBNA can be useful diagnostically.

Although EBV can be isolated from clinical samples such as saliva by morphologic transformation of cord blood lymphocytes, it is a technically difficult procedure and is not readily available. No virus is synthesized in the cord lymphocytes; its presence is detected by fluorescent antibody staining of the nuclear antigen.

Treatment

No antiviral therapy is necessary for uncomplicated infectious mononucleosis. Acyclovir has little activity against EBV, but administration of high doses may be useful in life-threatening EBV infections.

Prevention

There is no EBV vaccine.

Association With Cancer

EBV infection is associated with cancers of lymphoid origin: Burkitts lymphoma in African children, other B-cell lymphomas, nasopharyngeal carcinoma in the Chinese population, and thymic carcinoma in the United States. The initial evidence of an association of EBV infection with Burkitt’s lymphoma was the production of EBV by the lymphoma cells in culture. In fact, this was how EBV was discovered by Epstein and Barr in 1964. Additional evidence includes the finding of EBV DNA and EBNA in the cells of nasopharyngeal and thymic carcinomas. EBV can induce malignant transformation in B lymphocytes in vitro.

In Burkitt’s lymphoma, oncogenesis is a function of the translocation of the c-myc oncogene to a site adjacent to an immunoglobulin gene promoter. This enhances synthesis of the c-myc protein, a potent oncoprotein. The c-myc protein is a transcriptional regulator that enhances the synthesis of kinases that activate the cell cycle.

HUMAN HERPESVIRUS 8 (KAPOSI’S SARCOMA–ASSOCIATED HERPESVIRUS)

In 1994, it was reported that a new herpesvirus, now known as human herpesvirus 8 (HHV-8), or Kaposi’s sarcoma–associated herpesvirus (KSHV), causes Kaposi’s sarcoma (KS), the most common cancer in patients with AIDS. The idea that a virus other than HIV is the cause of KS arose from epidemiologic data showing that KS was common in patients who acquired HIV sexually but rare in patients who acquired HIV via blood transfusion. A second virus transmitted sexually appeared likely to be the cause.

The initial evidence that HHV-8 was involved was the finding that most KS cells taken from AIDS patients contain the DNA of this virus, but tissues taken from AIDS patients without KS had very little viral DNA. The DNA of this virus was also found in KS cells that arose in non–HIV-infected patients. On DNA analysis, HHV-8 resembles the lymphotropic herpesviruses (e.g., EBV and herpesvirus saimiri) more than it does the neurotropic herpesviruses, such as HSV and VZV.

Additional support was provided by serologic studies showing that most HIV-infected patients with KS had antibodies to HHV-8, whereas considerably fewer HIV-infected patients without KS had antibodies to the virus, and very few patients with other sexually transmitted diseases, but who were not HIV-infected, had these antibodies. The current estimate of HHV-8 infection in the general population ranges from about 3% in the United States and England to about 50% in East Africa.

HHV-8 causes malignant transformation by a mechanism similar to that of other DNA viruses (e.g., human papillomavirus), namely, inactivation of a tumor suppressor gene. A protein encoded by HHV-8 called latency-associated nuclear antigen (LANA) inactivates RB and p53 tumor suppressor proteins, which causes malignant transformation of endothelial cells.

Transmission of HHV-8 occurs primarily via sex and by saliva, but it is also transmitted in transplanted organs such as kidneys and appears to be the cause of transplantation-associated KS. The DNA of HHV-8 is found in the cells of transplantation-associated KS but not in the cells of other transplantation-associated cancers.

KS in AIDS patients is a malignancy of vascular endothelial cells that contains many spindle-shaped cells and erythrocytes. The lesions are reddish to dark purple, flat to nodular, and often appear at multiple sites such as the skin, oral cavity, and soles (but not the palms) (Figure 37–10). Internally, lesions occur commonly in the gastrointestinal tract and the lungs. The extravasated red cells give the lesions their purplish color. HHV-8 also infects B cells, inducing them to proliferate and produce a type of lymphoma called primary effusion lymphoma.

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FIGURE 37–10 Kaposi’s sarcoma—note two raised reddish-purple lesions on the foot caused by human herpesvirus 8 (Kaposi’s sarcoma–associated virus). (Reproduced with permission from Usatine RP et al. The Color Atlas of Family Medicine. New York: McGraw-Hill, 2009. Copyright © 2009 by The McGraw-Hill Companies, Inc.)

Laboratory diagnosis of KS is often made by biopsy of the skin lesions. HHV-8 DNA and RNA are present in most spindle cells, but that analysis is not usually done. Virus is not grown in culture.

The type of treatment depends on the site and number of the lesions. Surgical excision, radiation, and systemic drugs, such as alpha interferon or vinblastine, can be used. There is no specific antiviral therapy and no vaccine against HHV-8.

POXVIRUSES

The poxvirus family includes three viruses of medical importance: smallpox virus, vaccinia virus, and molluscum contagiosum virus. Poxviruses are the largest and most complex viruses.

SMALLPOX VIRUS

Disease

Smallpox virus, also called variola virus, is the agent of smallpox, the only disease that has been eradicated from the face of the Earth. Eradication is due to the vaccine. There is concern regarding the use of smallpox virus as an agent of bioterrorism. Poxviruses of animal origin, such as cowpox and monkey pox, are described in Chapter 46.

Important Properties

Poxviruses are brick-shaped particles containing linear double-stranded DNA, a disk-shaped core within a double membrane, and a lipoprotein envelope. The virion contains a DNA-dependent RNA polymerase. This enzyme is required because the virus replicates in the cytoplasm and does not have access to the cellular RNA polymerase, which is located in the nucleus.

Smallpox virus has a single, stable serotype, which is the key to the success of the vaccine. If the antigenicity varied as it does in influenza virus, eradication would not have succeeded. Smallpox virus infects only humans; there is no animal reservoir.

Summary of Replicative Cycle

The following description of the replicative cycle is based on studies with vaccinia virus, as it is much less likely to cause human disease than smallpox virus. After penetration of the cell and uncoating, the virion DNA-dependent RNA polymerase synthesizes early mRNA, which is translated into early, nonstructural proteins, mainly enzymes required for subsequent steps in viral replication. The viral DNA then is replicated, after which late, structural proteins are synthesized that will form the progeny virions. The virions are assembled and acquire their envelopes by budding from the cell membrane as they are released from the cell. Note that all steps in replication occur in the cytoplasm, which is unusual for a DNA virus.

Transmission & Epidemiology

Smallpox virus is transmitted via respiratory aerosol or by direct contact with virus either in the skin lesions or on fomites such as bedding.

Prior to the 1960s, smallpox was widespread throughout large areas of Africa, Asia, and South America, and millions of people were affected. In 1967, the World Health Organization embarked on a vaccination campaign that led to the eradication of smallpox. The last naturally occurring case was in Somalia in 1977.

Pathogenesis & Immunity

Smallpox begins when the virus infects the upper respiratory tract and local lymph nodes and then enters the blood (primary viremia). Internal organs are infected; then the virus reenters the blood (secondary viremia) and spreads to the skin. These events occur during the incubation period, when the patient is still well. The rash is the result of virus replication in the skin, followed by damage caused by cytotoxic T cells attacking virus-infected cells.

Immunity following smallpox disease is lifelong; immunity following vaccination lasts about 10 years.

Clinical Findings

After an incubation period of 7 to 14 days, there is a sudden onset of prodromal symptoms such as fever and malaise. This is followed by the rash, which is worse on the face and extremities than on the trunk (i.e., it has a centrifugal distribution). The rash evolves through stages from macules to papules, vesicles, pustules, and, finally, crusts in 2 to 3 weeks.

Laboratory Diagnosis

In the past when the disease occurred, the diagnosis was made either by growing the virus in cell culture or chick embryos or by detecting viral antigens in vesicular fluid by immunofluorescence.

Prevention

The disease was eradicated by global use of the vaccine, which contains live, attenuated vaccinia virus. The success of the vaccine is dependent on five critical factors: (1) smallpox virus has a single, stable serotype; (2) there is no animal reservoir, and humans are the only hosts; (3) the antibody response is prompt, and therefore exposed persons can be protected; (4) the disease is easily recognized clinically, and therefore exposed persons can be immunized promptly; and (5) there is no carrier state or subclinical infection.

The vaccine is inoculated intradermally, where virus replication occurs. The formation of a vesicle is indicative of a “take” (success). Although the vaccine was relatively safe, it became apparent in the 1970s that the incidence of side effects such as encephalitis, generalized vaccinia, and vaccinia gangrenosa exceeded the incidence of smallpox. Routine vaccination of civilians was discontinued, and it is no longer a prerequisite for international travel. Military personnel are still vaccinated.

In response to the possibility of a bioterrorism attack using smallpox virus, the U.S. federal government has instituted a program to vaccinate “first responders” so that they can give emergency medical care without fear of contracting the disease. To protect the unimmunized general population, the concept of “ring vaccination” will be used. This is based on the knowledge that an exposed individual can be immunized as long as 4 days after exposure and be protected. Therefore, if an attack occurs, people known to be exposed will be immunized as well as the direct contacts of those people and then the contacts of the contacts, in an expanding ring. Several military personnel and civilians have experienced myocarditis following vaccination, and as of this writing, caution has been urged regarding expanding this program to the general population.

Vaccinia immune globulins (VIG), containing high-titer antibodies against vaccinia virus, can be used to treat most of the complications of vaccination. In the past, methisazone was used to treat the complications of vaccination and could be useful again. Rifampin inhibits viral DNA-dependent RNA polymerase but was not used clinically against smallpox.

MOLLUSCUM CONTAGIOSUM VIRUS

Molluscum contagiosum virus (MCV) is a member of the poxvirus family but is quite distinct from smallpox and vaccinia viruses. The lesion of molluscum contagiosum is a small (2–5 mm), flesh-colored papule on the skin or mucous membrane that is painless, nonpruritic, and not inflamed (Figure 37–11). The lesions have a characteristic cup-shaped (umbilicated) crater with a white core. The lesion is composed of hyperplastic epithelial cells within which a cytoplasmic inclusion body can be seen. The inclusion body contains progeny MCV.

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FIGURE 37–11 Molluscum contagiosum—note two fleshy papular lesions under the eye caused by molluscum contagiosum virus, a member of the poxvirus family. (Reproduced with permission from Usatine RP et al. The Color Atlas of Family Medicine. New York: McGraw-Hill, 2009. Copyright © 2009 by The McGraw-Hill Companies, Inc.)

Note that these lesions are different from warts, which are caused by papillomavirus, a member of the papovavirus family.

MCV is transmitted by close personal contact, including sexually. The disease is quite common in children, in whom lesions often occur around the eyes and on the trunk. Adults often have lesions in the genital area. The lesions can be large and numerous in patients with reduced cellular immunity, such as AIDS patients. In immunocompetent patients, the lesions are self-limited but may last for months.

The diagnosis is typically made clinically; the virus is not isolated in the clinical laboratory, and antibody titers are not helpful. Removal of the lesions by curettage or with liquid nitrogen is often effective. There is no established antiviral therapy, but cidofovir may be useful in the treatment of the extensive lesions that occur in immunocompromised patients. In AIDS patients, antiretroviral therapy may restore sufficient immunity to cause the lesions to resolve. There is no vaccine.

HEPADNAVIRUSES

HEPATITIS B VIRUS

Hepatitis B virus, a DNA enveloped virus, is described in Chapter 41 with the other hepatitis viruses.

SELF-ASSESSMENT QUESTIONS

1. Your patient is a 30-year-old man who has frequent episodes of herpes labialis. He asks you to tell him something about herpes simplex virus type 1 (HSV-1). Which one of the following would be the most accurate statement to make?

(A) Acyclovir can eradicate the latent state of HSV-1 but not HSV-2.

(B) The main site of latency by HSV-1 is the neurons in the sensory ganglia of the face.

(C) HSV-1 is an enveloped virus that has a DNA genome and a DNA polymerase in the virion.

(D) The lesions of primary HSV-1 infections are less extensive and less severe than the lesions of recurrent HSV-1 infections.

(E) The laboratory diagnosis of HSV-1 infections typically involves the detection of a greater than fourfold rise in antibody titer against the virus.

2. Your patient is a woman who is due to give birth next week. She asks you about the risk of her baby becoming infected with herpes simplex virus type 2 (HSV-2). Which one of the following is the most accurate response?

(A) HSV-2 is a significant cause of congenital abnormalities.

(B) The risk is higher if the mother has visible lesions than if she does not.

(C) The risk is higher if the mother has IgG antibody to HSV-2 than if she has IgM antibody.

(D) The risk is higher if the delivery occurs by cesarean section than if the delivery is performed vaginally.

(E) The risk is higher if the mother is having an episode of recurrent disease caused by HSV-2 than if it were a primary episode.

3. Regarding varicella-zoster virus (VZV), which one of the following is most accurate?

(A) High-dose acyclovir can eliminate the latent state caused by VZV.

(B) The principal site of latency of VZV is in the nucleus of motor neurons.

(C) Domestic animals, such as pigs and chickens, are the main reservoir for VZV.

(D) The vaccine against varicella contains all three serotypes of formalin-killed VZV as the immunogen.

(E) When zoster occurs in an immunocompromised patient, acyclovir should be given to prevent disseminated infection.

4. Regarding cytomegalovirus (CMV), which one of the following is most accurate?

(A) CMV is usually acquired by the fecal–oral route in adults.

(B) Neonates born from infected mothers should be given the subunit vaccine.

(C) Reactivation of CMV in sensory ganglion cells leads to painful vesicles along nerves.

(D) Lamivudine should be used to treat CMV infections in immunocompromised patients.

(E) CMV infection of a fetus during the first trimester results in more congenital abnormalities than infection in the third trimester.

5. Regarding Epstein–Barr virus (EBV) and infectious mononucleosis, which one of the following is most accurate?

(A) EBV enters the latent state primarily in CD4-positive helper T cells.

(B) Approximately 10% of people in the United States have been exposed to EBV.

(C) People with infectious mononucleosis produce antibodies that agglutinate sheep red cells.

(D) The atypical lymphs in the blood of people with infectious mononucleosis are EBV-infected T helper cells.

(E) Patients with deficient cell-mediated immunity should receive passive–active immunization against EBV.

6. Naturally occurring smallpox disease has been eradicated from the face of the Earth. Eradication was achieved by the use of the vaccine. Regarding this vaccine, which one of the following is the most accurate?

(A) The vaccine should be given in conjunction with preformed antibody to the virus.

(B) Administration of the vaccine 1 day after exposure to the virus does not protect against disease.

(C) The vaccine contains killed smallpox virus so the virus in the vaccine does not cause adverse effects.

(D) Smallpox virus has a single stable serotype, so new formulations of the vaccine do not have to be made each year.

(E) Because domestic animals such as cows are the main reservoir for smallpox virus, the vaccine must interrupt transmission from these sources.

7. Your patient is a 35-year-old man who had a grand-mal seizure this morning. Magnetic resonance imaging revealed a lesion in the temporal lobe. A brain biopsy showed multinucleated giant cells with intranuclear inclusion bodies. Which one of the following is the most likely cause of this disease?

(A) Cytomegalovirus

(B) Epstein–Barr virus

(C) Herpes simplex virus type 1

(D) Human herpesvirus 8

(E) Varicella-zoster virus

8. Regarding the patient in Question 7, which one of the following is the best choice of drug to treat his infection?

(A) Acyclovir

(B) Lamivudine

(C) Oseltamivir

(D) Ritonavir

(E) Zidovudine

9. Your patient is a 22-year-old woman with several episodes of bloody diarrhea. She is HIV antibody positive with a CD4 count of 50. Stool cultures for Shigella, Salmonella, and Campylobacter were negative. An assay for Clostridium difficile toxin was negative. Colonoscopy revealed many ulcerated lesions. Biopsy revealed cells with “owl’s eye” inclusions in the nucleus. Which one of the following is the most likely cause of this disease?

(A) Cytomegalovirus

(B) Epstein–Barr virus

(C) Herpes simplex virus type 1

(D) Human herpesvirus 8

(E) Varicella-zoster virus

10. Regarding the patient in Question 9, which one of the following is the best choice of drug to treat her infection?

(A) Amantadine

(B) Enfuvirtide

(C) Ganciclovir

(D) Nevirapine

(E) Ribavirin

ANSWERS

1. (B)

2. (B)

3. (E)

4. (E)

5. (C)

6. (D)

7. (C)

8. (A)

9. (A)

10. (C)

SUMMARIES OF ORGANISMS

Brief summaries of the organisms described in this chapter begin on page 648. Please consult these summaries for a rapid review of the essential material.

PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS

Questions on the topics discussed in this chapter can be found in the Clinical Virology section of PART XIII: USMLE (National Board) Practice Questions starting on page 703. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.

1Note the similarity between latency with herpesviruses and lysogeny with bacteriophage (discussed in Chapter 29).