Herpesvirus Replication
المؤلف:
Stefan Riedel, Jeffery A. Hobden, Steve Miller, Stephen A. Morse, Timothy A. Mietzner, Barbara Detrick, Thomas G. Mitchell, Judy A. Sakanari, Peter Hotez, Rojelio Mejia
المصدر:
Jawetz, Melnick, & Adelberg’s Medical Microbiology
الجزء والصفحة:
28e , p474-475
2025-11-08
58
The replication cycle of HSV is summarized in Figure 1. The virus enters the cell by fusion with the cell membrane after binding to specific cellular receptors via envelope glycoproteins. Several herpesviruses bind to cell surface glycosaminoglycans, principally heparan sulfate. Virus attachment also involves binding to one of several coreceptors (eg, members of the immunoglobulin superfamily). After fusion, the capsid is transported through the cytoplasm to a nuclear pore, uncoating occurs, and the DNA becomes associated with the nucleus. The viral DNA forms a circle immediately upon release from the capsid. Expression of the viral genome is tightly regulated and sequentially ordered in a cascade fashion. VP16, a tegument protein, complexes with several cellular proteins and activates initial viral gene expression. Immediate-early genes are expressed, yielding “α” proteins. These proteins permit expression of the early set of genes, which are translated into “β” proteins. Viral DNA replication begins, and late transcripts are produced that give rise to “γ” proteins. More than 50 different proteins are synthesized in herpes virus-infected cells. Many α and β proteins are enzymes or DNA-binding proteins; most of the γ proteins are structural components.
Fig1. Replication cycle of herpes simplex virus. (1) Virus fuses with plasma membrane, and viral DNA is released from capsid at nuclear pore followed by circularization of genome and transcription of immediate-early genes. (2) α-Proteins, products of immediate-early genes, stimulate transcription of early genes. (3) β-Proteins, products of early genes, function in DNA replication, yielding concatemeric DNA. Late genes are transcribed. (4) γ-Proteins, products of late genes and consisting primarily of viral structural proteins, participate in virion assembly. Unit-length viral DNA is cleaved from concatemers and packaged into capsids. Enveloped viral particles accumulate in the endoplasmic reticulum (ER) and are transported from the cell. (Reproduced with permission from Willey JM, Sherwood LM, Woolverton CJ: Prescott, Harley, and Klein’s Microbiology, 7th ed. McGraw-Hill, 2008. © McGraw-Hill Education.)
Viral DNA is transcribed throughout the replicative cycle by cellular RNA polymerase II but with the participation of viral factors. Viral DNA is synthesized by a rolling circle mechanism. Herpesviruses differ from other nuclear DNA viruses in that they encode a large number of enzymes involved in DNA synthesis. These enzymes have been good targets for development of antiviral drugs. Newly synthesized viral DNA is packaged into preformed empty nucleocapsids in the cell nucleus.
Maturation occurs by budding of nucleocapsids through the altered inner nuclear membrane. Enveloped virus particles are then transported by vesicular movement to the surface of the cell.
The length of the replication cycle varies from about 18 hours for HSV to more than 70 hours for CMV. Cells productively infected with herpesviruses are invariably killed. Host macromolecular synthesis is shut off early in infection; normal cellular DNA and protein synthesis virtually stop as viral replication begins. Cytopathic effects induced by human herpesviruses are quite distinct and can include intranuclear inclusion bodies (Figure 2).
Fig2. Cytopathic effects induced by herpesviruses. A: Herpes simplex virus in HEp-2 cells (hematoxylin and eosin stain, 57×), with early focus of swollen, rounded cells. B: Varicella-zoster virus in human kidney cells (hematoxylin and eosin stain, 228×), with multinucleated giant cell containing acidophilic intranuclear inclusions (arrow). C: Cytomegalovirus in human fibroblasts (unstained, 35×) with two foci of slowly developing cytopathic effect. D: Cytomegalovirus in human fibroblasts (hematoxylin and eosin stain, 228×), showing giant cells with acidophilic inclusions in the nuclei (small arrow) and cytoplasm (large arrow), the latter being characteristically large and round. (Courtesy of I Jack; reproduced from White DO, Fenner FJ: Medical Virology, 3rd ed. Academic Press, 1986.)
The number of potential protein-coding open-reading frames in herpesvirus genomes ranges from about 70 to more than 200. In the case of HSV, about half of the genes are not needed for growth in cultured cells. The other genes are probably required for viral survival in vivo in natural hosts.
Herpesviruses have been found to express multiple microRNAs, small (∼22 nucleotides) single-stranded RNAs that function posttranscriptionally to regulate gene expression. These viral microRNAs are important in regulating cellular functions and entry into or exit from (or both) the latent phase of the virus life cycle and provide attractive targets for novel antiviral therapy development.
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