Eight human herpesvirus species are known. All have the ability to enter a latent state following primary infection of their natural host and be reactivated at a later time. However, the exact molecular nature of the latency and the frequency and manifestation of reactivation vary with the type of herpesvirus.

A. Structure of herpesviruses

 Herpesvirus virions consist of an icosahedral capsid enclosed in an envelope derived from the host’s nuclear membrane (Figure 1). Between the envelope and the capsid lies an amorphous proteinaceous material called tegument, which contains virus-encoded enzymes and transcription factors essential for initiation of the infectious cycle, although none of these is a polymerase. The genome is a single molecule of linear, double-stranded DNA, encoding from 70 to 200 proteins, depending on the species. Although all members of the family have some genes with homologous functions, there is little nucleotide sequence conservation and little antigenic relatedness between species.

Fig1. Structure of herpesvirus. A. Schematic drawing. B. Transmission electron micrograph.

B. Classification of herpesviruses

 Herpesviridae cannot readily be differentiated by morphology in the electron microscope, because they all have similar appearances. However, Herpesviridae have been divided into three subfamilies, based primarily on biologic characteristics.

1. Alphaherpesvirinae (herpes simplex virus group):

These viruses have a relatively rapid, cytocidal or lytic growth cycle and establish dormant or latent infections in nerve ganglia. Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV) belong to this group. HSV-1 and HSV-2 share significant nucleotide homology and, therefore, share many common features in replication and pathogenesis. VZV has a smaller genome than HSV, but the two viruses have many genes that share sequence identity.

 2. Betaherpesvirinae (cytomegalovirus group):

These viruses have a relatively slow replication cycle that results in the formation of characteristic, multinucleated, giant host cells. Latency is established in nonneural tissues, primarily lymphoreticular cells and glandular tissues. Human cytomegalovirus (HCMV) and human herpesviruses types 6 and 7 (HHV-6 and HHV-7) are in this group.

 3. Gammaherpesvirinae (lymphoproliferative group):

 These viruses replicate in mucosal epithelium and establish latent infections primarily in B cells. They induce cell proliferation in and immortalize lymphoblastoid cells. Epstein-Barr virus (EBV) was previously the only well-characterized human gammaherpesvirus. However, genome analysis of a virus recovered from cells of Kaposi sarcoma (KS) revealed it to also be a human member of the Gammaherpesvirinae. It has been designated human herpesvirus type 8 (HHV-8). HHV-8 can also establish latency and immortalize endothelial cells.

 C. Replication of the herpesviruses

Herpesviruses replicate in the nucleus, following the basic pattern of DNA virus replication. Regulation of herpesvirus transcription is referred to as “cascade control,” in that expression of a first set of genes is required for expression of a second set, which, in turn, is required for expression of a third set of genes. [Note: A similar pattern is found in some other DNA virus families in which the genes are referred to as immediate early, delayed early, and late.] The general features of herpesvirus replication are summarized in Figure 2.

Fig2. Replication of herpesviruses.

1. Virus adsorption and penetration: Herpesviruses adsorb to host cell receptors that can differ according to the virus species and the tissue type being infected. Viral envelope glycoproteins pro mote fusion of the envelope with the cell’s plasma membrane, depositing the nucleocapsid and tegument proteins in the cytosol. One of the tegument proteins is a general RNase that efficiently degrades all mRNAs, effectively shutting off host cell protein synthesis. Because this protein’s nucleolytic activity occurs prior to the onset of viral mRNA synthesis, it is selective for host RNAs.

 2. Viral DNA replication and nucleocapsid assembly: The nucleocapsid is transported to a nuclear pore, through which viral DNA is released into the nucleus. Another tegument protein is an activator of cellular RNA polymerase that causes the enzyme to initiate transcription of the set of viral immediate early genes, which code for a variety of regulatory functions, including initiation of further gene transcription. Delayed early genes are expressed next, and they code primarily for enzymes that are required for replication of viral DNA, such as viral DNA polymerase, helicase, and thymidine kinase. Because these enzymes are virus specific, they provide excellent targets for antiherpes agents (such as acyclovir), which are relatively nontoxic for the cell. As is the case with other DNA viruses, late genes code for structural proteins of the virion and proteins involved in assembly and maturation of viral progeny.

3. Viral envelope acquisition: Newly synthesized envelope proteins accumulate in patches on the nuclear membrane, and nucleocapsids that have been assembled in the nucleus acquire their envelopes by budding through these patches. The completed virus is transported by a vacuole to the surface of the cell. Additional copies of the envelope glycoproteins are also trans ported to the plasma membrane, which acquires herpesvirus anti genic determinants. These glycoproteins may also cause fusion of neighboring cells, in some cases producing characteristic multinucleated giant cells. The end result of this productive, lytic cycle is cell death because most cellular synthetic pathways are effectively turned off during viral replication.

 4. Latency: All herpesviruses can undergo an alternative infection cycle, entering a quiescent, dormant state (latency) from which they can subsequently be reactivated. The cell type in which this occurs is usually not the same cell type in which productive, lytic infection occurs. For each of the herpesviruses, the mechanism of latency, nature of the host cells, frequency of reactivation, and the nature of the recurrent disease are characteristic. Therefore, the topic of latency is discussed in this chapter in the context of the individual virus species.

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مواضيع ذات صلة

Epstein-Barr Virus

Herpes simplex virus, types 1 and 2

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)