HSV-1 and HSV-2 are the only human herpesviruses that have a significant degree of nucleotide sequence identity (about 50 percent). Therefore, they share many common features in replication, disease production, and latency.

A. Epidemiology and pathogenesis

Transmission of both HSV types is by direct contact with virus-containing secretions or with lesions on mucosal or cutaneous surfaces. Primary or recurrent infections in the oropharyngeal region, caused primarily by HSV-1, are accompanied by virus release into saliva, and kissing and saliva-contaminated fingers are major modes of transmission. In genital tract infections, caused primarily by HSV-2, virus is present in genital tract secretions. Consequently, sexual intercourse and passage of newborns through the birth canal of infected mothers are major modes of transmission. Both HSV-1 and HSV-2 multiply in epithelial cells of the mucosal surface onto which they have been inoculated, resulting in production of vesicles or shallow ulcers containing infectious virus. In immunocompetent individuals, epithelial infection remains localized because cytotoxic T lymphocytes recognize the HSV-specific antigens on the surface of infected cells and kill these cells before progeny virus has been produced. A lifelong latent infection is usually established in the regional ganglia as a result of entry of infectious virions into sensory neurons that terminate at the site of the infection.

B. Clinical significance

A generality (albeit of limited use) is that HSV-1 is most commonly found in lesions above the waist, and HSV-2 is more commonly the cause of lesions below the waist. However, HSV-1 can infect the genital tract, causing similar lesions, and, similarly, HSV-2 can cause lesions in the oral cavity.

1. Primary infections of the upper body: Many primary HSV infections are subclinical, but the most common symptomatic infections of the upper body are gingivostomatitis in young children (Figure 1) and pharyngitis or tonsillitis in adults. The painful lesions typically consist of vesicles and shallow ulcers, which are often accompanied by systemic symptoms, such as fever, malaise, and myalgia. Another clinically important site of infection is the eye, in which keratoconjunctivitis can lead to corneal scar ring and eventual blindness. If HSV infection spreads to the central nervous system (CNS), it can cause encephalitis, which, if untreated, has a mortality rate estimated to be 70 percent. Survivors are usually left with neurologic deficits. In the United States, HSV-1 infection of the eye is the second most common cause of corneal blindness (after trauma). HSV infections of the CNS account for up to 20 percent of encephalitis viral infections.

Fig1. Herpes simplex stomatitis.

 2. Primary infections of the genital tract: Primary genital tract lesions are similar to those of the oropharynx. However, based on the frequency of antibody in the population, the majority of these infections are asymptomatic. When symptomatic (genital herpes), local symptoms include painful vesiculo-ulcerative lesions on the vulva, cervix, and vagina in women and the penis in men. Systemic symptoms of fever, malaise, and myalgia may be more severe than those that accompany primary oral cavity infections. In pregnant women with a primary genital HSV infection, the risk of infecting the newborn during birth is estimated to be 30 to 40 percent (neonatal herpes). Because such infants have no pro tective maternal antibody, a disseminated infection, often involving the CNS, may result. There is a high mortality rate if untreated, and survivors are likely to have permanent neurologic sequelae. A newborn is also at risk of acquiring infection from an infected mother by transfer on contaminated fingers or in saliva. However, infection in utero appears to occur only rarely.

3. Latency: In latently infected cells of the ganglia—HSV-1 in trigeminal ganglia and HSV-2 in sacral or lumbar ganglia—from one to thousands of copies of the viral genome are present as nonintegrated, circular molecules of DNA in the nuclei (Figure 2). A limited number of viral genes are expressed during latency. These transcripts (called LATS for latency-associated transcripts) sup press production of progeny virus.

Fig2. Primary and recurrent herpes simplex infections.

4. Reactivation: Several factors, such as hormonal changes, fever, and physical damage to the neurons, are known to induce reactivation and replication of the latent virus (see Figure 2). The newly synthesized virions are transported down the axon to the nerve endings from which the virus is released, infecting the adjoining epithelial cells. Characteristic lesions are thus produced in the same general area as the primary lesions. [Note: Virus replication occurs in only a fraction of the latently infected neurons, and these nerve cells eventually die.] The presence of circulating antibody does not prevent this recurrence but does limit the spread of virus to surrounding tissue. Sensory nerve symptoms, such as pain and tingling, often precede and accompany the appearance of lesions. In general, the severity of any systemic symptoms is considerably less than that of a primary infection, and many recurrences are characterized by shedding of infectious virus in the absence of visible lesions.

a. Herpes simplex virus type 1: The frequency of oropharyngeal symptomatic recurrences is variable, ranging from none to several a year. The lesions occur as clusters of vesicles at the border of the lips (herpes labialis, or “cold sores” or “fever blisters”) and heal without scarring in 8 to 10 days.

b. Herpes simplex virus type 2: Reactivation of HSV-2 genital infections can occur with considerably greater frequency (for example, monthly) and is often asymptomatic but still results in viral shedding. Consequently, sexual partners or newborn infants may be at increased risk of becoming infected resulting from lack of precautions against transmission. The risk of transmission to the newborn is much less than in a primary infection because considerably less virus is shed and the baby has some maternal anti-HSV antibody. This antibody also lessens the severity of the disease if infection does occur.

C. Laboratory identification

Laboratory identification is not required for diagnosis of characteristic HSV lesions in normal individuals. Identification is important, however, to prevent neonatal infection and HSV encephalitis and keratoconjunctivitis, in which early initiation of therapy is essential, yet characteristic lesions are not present. Further, for purposes of therapy in the immunocompromised patient, HSV infection must be distinguished from that of VZV. It must also be distinguished from similar exanthems (skin eruptions) caused by other viruses or, in some cases, by bacteria or noninfectious, allergy-based reactions. Demonstration of HSV by inoculation of human cell tissue culture with a sample of vesicle scraping, fluid, or genital swab is the definitive method for demonstrating infection. The presence of the virus can result in syncytia formation between cells and the formation of Cowdry type A bodies within the host cell nucleus. Gross cytopathic changes may require several days to appear, but individual infected cells can be detected within 24 hours by use of immunofluorescence or immunoperoxidase staining with antibodies directed against viral early proteins. Using these same techniques, infected cells can also be demonstrated directly in clinical specimens, although this approach is generally less sensitive than virus isolation in tissue culture. Direct detection of viral DNA by hybridization techniques complements these procedures and, after amplification of the DNA by polymerase chain reaction [PCR] , is considerably more sensitive. For example, in patients with encephalitis, HSV etiology can be confirmed by demonstration of viral DNA in the cerebral spinal fluid (CSF) instead of by brain biopsy.

D. Treatment

The guanine analog, acycloguanosine (acyclovir), is selectively effective against HSV because it becomes an active inhibitor of DNA synthesis only after initially being phosphorylated by the HSV thymidine kinase (Figure 3). The drug of choice for any primary HSV infection, acyclovir is especially important in treating herpes encephalitis, neonatal herpes, and disseminated infections in immunocompromised patients. Other drugs effective in treating her pes simplex infection include famciclovir and topical penciclovir (Figure 4). Famciclovir is a prodrug that is metabolized to the active penciclovir. It provides more convenient dosing and greater bioavailability than oral acyclovir. Penciclovir is active against HSV 1, HSV-2, and VZV. None of these drugs can cure a latent infection, but they can minimize asymptomatic viral shedding and recurrences of symptoms (Figure 5).

Fig3. Mechanism of action of acyclovir.

Fig4. Drug therapy for herpes simplex infection. 1 Indicates first-line drugs; 2 indicates alternative drugs.

Fig5. Chronic suppressive antiviral therapy reduces the frequency of asymptomatic herpes simplex virus shedding.

 E. Prevention

Prevention of HSV transmission is enhanced by avoidance of contact with potential virus-shedding lesions and by safe sexual practice. Although prevention of neonatal HSV infections is important, genital infection of the mother can be difficult to detect because it is often asymptomatic. When overt genital tract lesions are detected at the time of delivery, cesarean section is usually warranted. Prophylactic therapy of the mother and the newborn with acyclovir can be employed if the presence of HSV is detected just before or at the time of birth. Measures to prevent physical transmission following birth are also important. A vaccine is not currently available.

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مواضيع ذات صلة

Epstein-Barr Virus

Herpesviridae: Structure and Replication

Adenoviridae

Human Cowpox

Human Monkeypox

Smallpox virus

Papovaviridae: Subfamily Polyomavirinae

Effects of viral infection on the host cell

Assembly and release of progeny viruses

Clinical Syndromes of Adenovirus

JCPyV and progressive multifocal leukoencephalopathy (PML)

Polyomavirus-associated nephropathy (PVAN)