Herpes Simplex Virus Virion Host Shutoff Protein: Immune Evasion Mediated by a Viral RNase?

Herpes simplex virus type 1 (HSV-1) is the prototypical member of the Herpesviridae, a large family of enveloped DNA viruses that infect diverse metazoans. It is also the defining example of the Alphaherpesvirinae, the neurotropic subfamily of herpesviruses. Like all herpesviruses, HSV displays both lytic and latent modes of interaction with its natural human host. Primary infection of epithelial cells produces the lytic response—virus replication followed by cell death. Progeny virus particles then infect adjacent sensory neurons, establishing a lifelong latent interaction. The latent viral genome is maintained in an extrachromosomal state in which only a restricted portion of the genome is transcribed. Latent genomes occasionally reactivate into the lytic cycle, producing a limited amount of progeny virus that gives rise to secondary infections of the epithelial sites enervated by the latently infected neurons. HSV executes a complex genetic program during lytic infection (reviewed in reference 47). Expression of most cellular genes is strongly suppressed, and three temporal classes of viral genes are sequentially activated in a regulatory cascade. Five viral immediate-early (IE) genes are expressed first, and four of these (ICP0, ICP4, ICP22, and ICP27) encode regulatory proteins that stimulate expression of the viral early (E) and late (L) genes. The E genes are activated next, giving rise to proteins required for replication of the viral genome. Viral DNA replication then ensues, augmenting IE-dependent expression of the L genes that encode the structural components of the virion. HSV differs from many other nuclear DNA viruses in that some of its key regulatory polypeptides are delivered into the host cell by the infecting virus particle. These virion regulators are located in the viral tegument—the space between the envelope and the nucleocapsid—and as such are injected into the newly infected cell immediately upon fusion of the viral envelope with the host cell plasma membrane. These proteins are therefore strategically poised to influence the very earliest events in the viral replication cycle. In the best-known case, the abundant tegument protein VP16 activates transcription of the viral IE genes, thereby contributing to the initial launch of the lytic program of gene expression (reviewed in reference 17). The tegument also contains vhs, the virion host shutoff protein encoded by HSV gene UL41. vhs is an mRNA-specific RNase that triggers rapid shutoff of host cell protein synthesis, disruption of preexisting polyribosomes, and degradation of host mRNAs in the absence of de novo viral gene expression (reviewed in reference 55). Here I summarize our present understanding of the mechanism of vhs action and discuss recent studies that point to intriguing roles in viral pathogenesis and immune evasion. Space limitations preclude an exhaustive review of the earlier literature; I therefore seek the indulgence of my colleagues and refer the interested reader to a recent review (55) and the introductory sections of two recent articles (9, 10) for more details. Unless otherwise stated below, vhs refers to the UL41 gene product of HSV-1.

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