Ebv

186 kbp TRi ,Rl|Rs TRg

162 kbp

Fig. 20-2 Genome structure of human herpesviruses Most human herpesvirus genomes comprise two regions designated long (L) and short (S) Terminal repeat ('I R) and internal lepeal (IR) sequences may bracket unique sequences (U,, Us) of both L and S (HSV) or only S regions (VZV). Repeat sequences are shown as boxes and are inverted as indicated by the direction of the arrows The repeat sequences allow the DNA they bracket to invert relative to the rest of the genome such that where both U, and Us are bracketed by repeat sequences, four isomers are made and packaged in equimolar amounts into virions Where only S is bracketed by repeat sequences (VZV) two equimolar isomers are made The genome of Epstein-Barr virus contains terminal repeat and major internal repeat (MIR) sequences in a variable number of copies Unique sequences (U, and Ucj are demarcated by these repeat families Near the extremities of U, are two regions, DK and D,, whose sequences are almost identical. The genome of human cytomegalovirus has a structure similar to that of HSV in the layout of repeats and unique sequences; it occurs in four isomers but is much larger. The genome of HHV-6 is still being investigated but appeal s to consist of a single unique sequence flanked by a pair of large direct repeats. [Based on D J McGeoch, Si-nun Vm>/ 3, 402 (1992).J

Classification

Subdivision of the family info three subfamilies was originally based on biological properties (see Table 20-1). The subfamily Alphaherpesvirinae includes herpes simplex virus types 1 and 2 and varicella-zoster virus. They all grow rapidly, lyse infected cells, and establish latent infections in sensory nerve ganglia. The subfamily Bcfalwrpcsvirinae includes human cytomegalovirus and HHV-6. Their replication cycle is slow and produces large, often multinucleate cells (cytomegalia). The viral genome remains latent in lyrnphoreticular tissue, secretory glands, kidneys, and other tissues. The subfamily Gainmaher-pt'svinme contains the Epstein-Barr virus. It replicates in lymphoid cells and may also be cytocidal for epithelial cells. Latency is frequently demonstrable in lymphoid tissue. As the genomes of an increasing number of herpesviruses are sequenced, herpesvirus taxonomy will progressively be based on the conservation of particular genes and gene clusters, the gene order, and the arrangement of the terminal sequences involved in packaging of the genome.

Viral Replication

Herpesvirus replication has been most extensively studied with herpes simplex virus (HSV); betaherpesviruses and gammaherpesviruses replicate more slowly and exhibit certain signilicant differences but generally follow a similar pattern. Unlike certain other DNA viruses such as papovaviruses and parvoviruses which stimulate the cellular DMA synthetic machinery, herpesviruses themselves encode most of the enzymes they require to increase the pool of deoxynucleotides and to replicate viral DNA. This facility is vital for viral replication in resting cells such as neurons, which throughout most of the life of the host never make DNA and do not divide. Interestingly, about half of the 73 genes of herpes simplex virus are not essential for viral replication in cultured cells, and it is likely that a similar ratio applies in other herpesviruses; presumably many of these additional genes encode regulatory proteins and virokines which optimize growth, dissemination, and pathogenicity in vivo by such devices as extending tissue tropism, establishing and maintaining latency, and suppressing the host immune response.

The HSV virion attaches via its envelope glycoprotein gC to the heparan sulfate moiety of cellular proteoglycans, then may form a firmer association between its gD glycoprotein and a second, unknown cellular receptor. Entry into the cytoplasm requires viral glycoproteins gB, gD, and gH and occurs by pH-independent fusion of the virion envelope with the plasma membrane. Tegument proteins are released, one of which shuts down cellular protein synthesis, and the capsid is transported along the cytoskeleton to a nuclear pore, where viral DNA is released, enters the nucleus, and circularizes.

Viral gene expression is tightly regulated, with three classes of mRNA, a, 0, and 7, being transcribed in strictly ordered sequence by the cellular RNA polymerase II (Fig. 20-3). Another of the released tegument proteins transacti-vates transcription of the five "immediate early" (a) genes. This viral protein associates with two cellular proteins to form a multiprotein complex that specifically recognizes a nucleotide sequence in the promoter region of the viral DNA, triggering transcription by the cellular polymerase. The a mRNAs are transported to the cytoplasm and translated to the several a proteins,

Fig. 20-3 Diagram representing transcription, translation, and DNA replication of herpes simplex virus (see lexl) Transcription and posttranscnptional processing occur in the nucleus, and translation in the cytoplasm Some of the a and 3 proleins are involved in lurther transonp tion, and some (3 proteins participate in DNA replication (Courtesy Dr 13 Roizman )

Fig. 20-3 Diagram representing transcription, translation, and DNA replication of herpes simplex virus (see lexl) Transcription and posttranscnptional processing occur in the nucleus, and translation in the cytoplasm Some of the a and 3 proleins are involved in lurther transonp tion, and some (3 proteins participate in DNA replication (Courtesy Dr 13 Roizman )

which are regulatory proteins that control the expression of all later genes. One a protein initiates transcription of the "early" ((J) genes. The (1 proteins are enzymes required to increase the pool of nucleotides (e.g., thymidine kinase, ribonucleotide reductase) and others needed for viral DNA replication (e g., a DNA polymerase, primase-helicase, topoisomerase, single-strand and double-strand DNA-binding proteins).

The viral genome probably replicates by a rolling circle mechanism. Following DNA replication, certain p proteins induce the program of transcription to switch again, and the resulting "late" (7) mRNAs are translated into the 7 proteins, most of which are structural proteins required for morphogenesis of the virion. Capsid proteins assemble to form empty capsids in the nucleus. Unit-length viral DNA cleaved from newly synthesized DNA concatemers is packaged to produce nucleocapsids, which then associate with patches of nuclear membrane to which tegument and glycosylated envelope proteins have bound. This triggers envelopment by budding through the nuclear membrane. Enveloped virions accumulate in endoplasmic reticulum, and the mature virions are released by exocytosis. Virus-specific proteins are also found in the plasma membrane, where they are involved in cell fusion, may act as Fc receptors, and are presumed to be targets for immune cytolysis.

Fig. 20-4 Cytopathic effects induced by herpesviruses (A) Herpes simplex virus in HEp-2 cells showing earty focal cyfopathology (hematoxylin and eosin stain, magnification. x40) (B) Varicella virus in human kidney cells (hematoxylin and eosin stain; magnification x 150), showing multinucleated giant cell containing acidophilic intranuclear inclusions (arrow) (C) Human cytomegalovirus in human fibroblasts (unstained, magnification x25), showing two foci of slowly developing cyfopathology. (D) Human cytomegalovirus in human fibroblasts (hematoxylin and eosin slain, magnification x 150), showing multinucleate giant cells with acidophilic inclusions in the nuclei (small arrow) and cytoplasm (large arrow), the latter being characteristically large and round (Courtesy 1 Jack )

Fig. 20-4 Cytopathic effects induced by herpesviruses (A) Herpes simplex virus in HEp-2 cells showing earty focal cyfopathology (hematoxylin and eosin stain, magnification. x40) (B) Varicella virus in human kidney cells (hematoxylin and eosin stain; magnification x 150), showing multinucleated giant cell containing acidophilic intranuclear inclusions (arrow) (C) Human cytomegalovirus in human fibroblasts (unstained, magnification x25), showing two foci of slowly developing cyfopathology. (D) Human cytomegalovirus in human fibroblasts (hematoxylin and eosin slain, magnification x 150), showing multinucleate giant cells with acidophilic inclusions in the nuclei (small arrow) and cytoplasm (large arrow), the latter being characteristically large and round (Courtesy 1 Jack )

Such productive infections (as opposed to latent infections) are lytic, as a result of virus-induced shutdown of host protein and nucleic acid synthesis. Major changes are obvious microscopically, notably marginatum and pulverization of chromatin and the formation of large eosinophilic intranuclear inclusion bodies, which are characteristic of herpesvirus infections and can usually be found both in herpesvirus-infected tissues and in appropriately stained cell cultures (Fig. 20-4).

Herpes Simplex Viruses

Pathogenesis and Immunity

Although preexisting neutralizing antibody directed against envelope glycoproteins, notably gB and gD, may successfully prevent primary infection and limit spread of herpes simplex virus from epithelial cells to nerve endings, cell-mediated immunity is the key to recovery from primary infection and maintenance of latency. At the site of epidermal infection viral antigens are presented on dendritic cells and macrophages to CD4+ Th, lymphocytes, which initiate viral clearance by secreting cytokines such as interferon -y (IFN-7) that recruit and activate macrophages and natural killer (NK) cells. CD4+ and CD8* T cells, as well as NK cells and antibody-dependent cell-mediated cytotoxicity (ADCC), lyse infected cells. The overt epithelial infection is cleared, but some virus ascends the local sensory neurons by retrograde axonal transport and establishes lifelong latency in the corresponding spinal or cerebral ganglion (see Figs. 10-1 and 10-2) The mechanism of establishment, maintenance, and reactivation of latency was discussed in Chapter 10. Experimental studies in animal models, as well as the clinical observation that immunocompromised humans are much more prone to severe HSV infections and to reactivation, make it clear that CD8+ T-cell-mediated immunity is the key to recovery from primary infection. HSV-specific CD8* T cells may also suppress the full expression of HSV DNA during the establishment of latency in sensory ganglia. We do not yet understand what is the common link between the apparently disparate events known to trigger reactivation (immunosuppression, "stress," trauma, ultraviolet irradiation, fever, etc.).

Recurrences of disease are typically less severe than primary disease, and the frequency and severity diminish with time. The two HSV types display a degree of selectivity in their tissue tropism. HSV-2 replicates to a higher titer than does HSV-1 in genital mucosa, is more likely to lead to encephalitis and severe mental impairment in neonates, is twice as likely as HSV-1 to establish reactivatable latent infection, and is subject to recur almost 10 times as frequently; the converse applies to orolabial infections, where HSV-1 predominates. There is also evidence of extraganglionic latency at the site of primary infection, for example, genital tract or cornea, but the nature and biological significance of this are unknown. The severity of primary HSV infection is influenced by three major factors: (1) age, premature infants being particularly vulnerable, (2) site, systemic and brain infections being much more serious than infections confined to epithelial surfaces, and (3) immunocompe-tence, T-cell-mediated immunity being crucial in the control of infection.

Two of the HSV glycoproteins, gF, and gl, form a receptor (or the Fc domain ol IgC This Fc receptor is found on the surface of both virions and infected cells and can protect both against immunologic attack, by steric hindrance resulting from binding of normal IgG, or from "bipolar bridging" of FISV antibody which can attach to gE/gl by its Fc end and simultaneously to another HSV glycoprotein via one Fab arm Moreover, gC is a receptor for the C3b component of complement and may protect infected cells from antibody-complement-mediated cytolysis.

Clinical Features

In considering the several clinical presentations it is important to distinguish between primary and recurrent infections (Table 20-3) Primary infections with HSV are generally inapparent, but when clinically manifest they tend to be more severe than are recurrences in the same dermatome. Since immunity to exogenous reinfection is long-lasting, nearly all second infections with the same HSV type are reactivations of an endogenous latent infection. However, because cross-immunity is only partial, reinfection with the heterologous serotype can occur (e.g., genital herpes caused by HSV-2 in an HSV-1 immune person); such cases are called "initial disease, nonprimary infection" and are usually mild.

Oropharyngeal Herpes Simplex

Primary infection with HSV-1 most commonly involves the mouth and/or throat (Fig. 20-5A,C). In young children the classic clinical presentation is gingivostomatitis. The mouth and gums become covered with vesicles which soon rupture to form ulcers. Though febrile, irritable, and in obvious pain with bleeding guns, the child recovers uneventfully. In adults, primary infection more commonly presents as a pharyngitis or tonsillitis.

Following recovery from primary oropharyngeal infection the individual

Table 20-3

Diseases Produced by Herpes Simplex Viruses

Primary (P) or

Table 20-3

Diseases Produced by Herpes Simplex Viruses

Primary (P) or

Disease

recurrent (R)

Age

Frequency

Severity

Type

Gingivostomatitis

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