Herpesviruses: introduction



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Virus

Primary Infection

Usual Site of Latency

Recurrent Infection

Route of Transmission

HSV-1

Gingivostomatitis1

Cranial sensory ganglia

Herpes labialis,2encephalitis, keratitis

Via respiratory secretions and saliva

HSV-2

Herpes genitalis, perinatal disseminated disease

Lumbar or sacral sensory ganglia

Herpes genitalis

Sexual contact, perinatal infection

VZV

Varicella

Cranial or thoracic sensory ganglia

Zoster2

Via respiratory secretions

EBV

Infectious mononucleosis1

B lymphocytes

None3

Via respiratory secretions and saliva

CMV

Congenital infection (in utero), mononucleosis

Uncertain4

Asymptomatic shedding2

Intrauterine infection, transfusions, sexual contact, via secretions (e.g., saliva and urine)

HHV-85

Uncertain6

Uncertain

Kaposi's sarcoma

Sexual or organ transplantation






1Primary infection is often asymptomatic.

2In immunocompromised patients, dissemination is common.

3The relationship of EBV infection to "chronic fatigue syndrome" and B-cell neoplasms is unclear.

4CMV may be latent within circulating lymphoid cells or epithelial cells.

5Also known as Kaposi's sarcoma–associated herpesvirus.

6A mononucleosis-like syndrome has been described. KS itself also can result from a primary infection.



Three of the herpesviruses, herpes simplex virus types 1 and 2 and varicella-zoster virus, cause a vesicular rash, both in primary infections and in reactivations. Primary infections are usually more severe than reactivations. The other two herpesviruses, cytomegalovirus and Epstein-Barr virus, do not cause a vesicular rash.

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 herpes simplex viruses 1 and 2, and varicella-zoster virus infect epithelial cells primarily and cause latent infection in neurons. The beta herpesviruses, consisting of cytomegaloviruses and human herpesvirus 6, infect and become latent in a variety of tissues. The gamma herpesviruses, consisting of Epstein-Barr virus and human herpesvirus 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.







Virus

Giant Cells Produced

Fetal or Neonatal Disease Important

Important Laboratory Diagnostic Technique

Antiviral Therapy Commonly Used

HSV-1

Yes

No

Culture

Acyclovir1

HSV-2

Yes

Yes

Culture

Acyclovir

VZV

Yes

No

Culture

Acyclovir2

CMV

Yes

Yes

Culture

Ganciclovir3

EBV

No

No

Heterophil

None

HHV-8

No

No

DNA probes

Alpha interferon






1Not used in recurrent herpes labialis.

2Not used in varicella in immunocompetent children.

3Used in CMV retinitis and other severe forms of disease.


Certain herpesviruses are suspected of causing cancer in humans; e.g., Epstein-Barr virus is associated with Burkitt's lymphoma and nasopharyngeal carcinoma, and human herpesvirus 8 is associated with Kaposi's sarcoma. Several herpesviruses cause cancer in animals, e.g., leukemia in monkeys and lymphomatosis in chickens (see Tumor Viruses, Chapter 43).


HERPES SIMPLEX VIRUSES (HSV)

Herpes simplex virus 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.







Site

Disease Caused by HSV-1

Disease Caused by HSV-2

Skin

Vesicular lesions above the waist

Vesicular lesions below the waist (especially genitals)

Mouth

Gingivostomatitis

Rare

Eye

Keratoconjunctivitis

Rare

Central nervous system

Encephalitis (temporal lobe)

Meningitis

Neonate

Rare

Skin lesions and disseminated infection

Dissemination to viscera in immunocompromised patients

Yes

Rare







Diseases

HSV-1 causes acute gingivostomatitis, recurrent herpes labialis (cold sores), keratoconjunctivitis, and encephalitis. HSV-2 causes genital herpes, neonatal herpes, and aseptic meningitis.

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. Humans are the natural hosts of both HSV-1 and HSV-2.

Summary of Replicative Cycle

HSV-1 attaches to the cell surface at the site of the receptor for fibroblast growth factor. After entry into the cell, the virion is uncoated and the genome DNA enters the nucleus. Within the nucleus, the incoming genome DNA changes its configuration from linear to circular. Early virus messenger RNA (mRNA) is transcribed by host cell RNA polymerase and then translated into early, nonstructural proteins in the cytoplasm. Two of these early proteins, thymidine kinase and DNA polymerase, are important because they are sufficiently different from the corresponding cellular enzymes to be involved in the action of antiviral drugs, e.g., acyclovir.

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, multiple copies of HSV-1 DNA are found in the cytoplasm of infected neurons. Only a few genes are transcribed, and none are translated into protein.

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, then migrates up the neuron 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 2–3 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. Recurrences frequently reappear at the same site.

  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. MRI 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. 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. 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.

  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 being shed (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.

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

Laboratory Diagnosis

The most important diagnostic procedure is isolation of the virus from the lesion by growth in cell culture. The typical cytopathic effect occurs in 1–3 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). A rapid diagnosis from skin lesions can be made 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 (see Color Plate 25). A rapid diagnosis of encephalitis can be made by detecting HSV-1 DNA in the spinal fluid using a PCR assay, but virus is rarely recovered from the spinal fluid. The diagnosis of neonatal herpes infection typically involves the use of viral cultures or PCR assay.



Color Plate 25

Herpes simplex type-2—Multinucleated giant cells in Tzanck smear. Arrow points to a multinucleated giant cell with approximately eight nuclei. Provider: CDC/Dr. Joe Miller.


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 for primary and recurrent genital herpes; it shortens the duration of the lesions and reduces the extent of shedding of the virus. 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. 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

Prevention 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.


VARICELLA-ZOSTER VIRUS (VZV)

Disease

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

Important Properties

VZV is structurally and morphologically identical 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 Herpes Simplex Viruses).

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, 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. After the host has recovered, the virus becomes latent,probably in the dorsal root ganglia. During latency, most—if not all—viral DNA is located in the cytoplasm rather than integrated into nuclear 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 andnerve 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 14–21 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. 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. Reye's 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.

ZOSTER

The occurrence of painful vesicles along the course of a sensory nerve of the head or trunk is the usual picture. 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.

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. 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, since antibody is already present.

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 and none have any effect on 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. 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. It also causes pneumonia and other diseases in immunocompromised patients and heterophil-negative mononucleosis in immunocompetent individuals.

Important Properties

CMV is structurally and morphologically identical 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 Herpes Simplex Viruses). 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 in leukocytes 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 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.

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. 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 and hepatitis, occur in a high proportion of immunosuppressed patients, e.g., those with renal and bone marrow transplants. In AIDS patients, CMV commonly infects the intestinal tract and causes intractable colitis. 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. If available, polymerase chain reaction (PCR)-based assays that detect viral nucleic acids are also useful. 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 owl's-eye shape (see Color Plate 26). 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.

Color Plate 26



Cytomegalovirus—Owl's-eye inclusion body. Arrow points to an "owl's-eye" inclusion body in the nucleus of an infected cell. Provider: CDC/Dr. Edwin Ewing, Jr.


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. 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.




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