Elsevier

Gene

Volume 271, Issue 2, 27 June 2001, Pages 117-130
Gene

Review
Regulation of herpes simplex virus gene expression

https://doi.org/10.1016/S0378-1119(01)00512-1Get rights and content

Abstract

Expression of the more than 80 individual genes of herpes simplex virus 1 (HSV-1) takes place in a tightly regulated sequential manner that was first described over 20 years ago. Investigations since that time have focused on understanding the mechanisms that regulate this orderly and efficient expression of viral genes. This review examines recent findings that have shed light on how this process is regulated during productive infection of the cell. Although the story is still not complete, several aspects of HSV gene expression are now clearer as a result of these findings. In particular, several new functions have recently been ascribed to some of the known viral regulatory proteins. The results indicate that the viral gene expression is regulated through transcriptional as well as post-transcriptional mechanisms. In addition, it has become increasingly clear that the virus has evolved specific functions to interact with the host cell in order to divert and redirect critical host functions for its own needs. Understanding the interactions of HSV and the host cell during infection will be essential for a complete understanding of how viral gene expression is regulated. Future challenges in the field will be to develop a complete understanding of the mechanisms that temporally regulate virus gene expression, and to identify and characterize the relevant interactions between the virus and the distinctive cell types normally infected by the virus.

Introduction

Herpes simplex virus (HSV) has played a major historical role in the development of our current understanding of eukaryotic gene regulation. Like other DNA viruses which use the host cell RNA polymerase for transcription of mRNA, HSV was at one time considered a good model system for investigating the complexities of gene expression. The studies in the early 1980s which defined and characterized the cis-acting regulatory elements of a ‘typical’ eukaryotic gene, the HSV-1 thymidine kinase gene, are considered classics in the field of eukaryotic gene regulation as well as in the herpesvirus research community (McKnight et al., 1981, McKnight et al., 1984, McKnight, 1982, McKnight and Kingsbury, 1982). Now, however, HSV and other DNA viruses for that matter are more likely to be studied by virologists interested in understanding the intricacies of the virus itself, rather than as a model for eukaryotic gene regulation. One reason for this change in focus is the remarkable advances, not the least of which are technological, that have been made over the last two decades in directly studying the eukaryotic genome. In addition, it has become increasing clear that the regulation of expression of a ‘eukaryotic’ gene differs depending on whether it is present in the genome of the cell or the genome of the virus. Thus, there are still formidable challenges to developing a complete picture of viral gene expression. In an interesting role reversal, it is now the ability to study the host eukaryotic cell in finer detail that provides the opportunity to address the crucial host cell–virus interactions that function to regulate the orderly and efficient expression of HSV genes during infection.

There have been numerous excellent reviews on the regulation of HSV gene expression, including several within the last few years (Hay and Ruyechan, 1992, Ward and Roizman, 1994, Wagner et al., 1995, Roizman and Sears, 1996). Exhaustive reviews covering all aspects of HSV biology can be found in Fields Virology (Roizman, 1996, Roizman and Sears, 1996, Whitley, 1996). The aim of the present review is not to duplicate these works (and in fact they will be referenced quite extensively), but rather to focus on findings that have been reported fairly recently. In particular, this review will examine how these observations are changing some of our views regarding the regulation of viral gene expression and the involvement of the host cell in this process. While one of the most fascinating aspects of HSV biology is the virus's ability to establish a state of latency in the neuron as part of its biological life cycle, this review will focus only on the regulation of viral gene expression during productive or lytic infection. This is not due to a lack of interest in the subject of latency, but to the enormity of the task when coupled with the subject of productive infection.

The double-stranded DNA genome of HSV type 1 is approximately 152,000 bp, consisting of two segments of unique DNA, referred to as the unique long (UL) and unique short (US) regions. These unique segments are flanked by inverted repeats of DNA (e.g. RL and RS for repeats flanking the UL and US, respectively), as shown in the schematic diagram in Fig. 1 (for review, see Roizman and Sears, 1996). More than 80 different genes are distributed throughout the genome on both strands; genes located in the inverted repeat regions are present in two copies. In general, each gene has its own promoter to direct transcription, although some transcripts share 3′ ends. The nomenclatures used by herpesvirologists over the years to designate HSV genes have been somewhat confusing since many genes and proteins were given different names by different investigators. Since the published sequence of the genome became available (McGeoch et al., 1985, McGeoch et al., 1988), it has become commonplace to refer to genes by their location in the genome, e.g. UL1-56, US1-11. Encoded proteins, even if assigned multiple names, are usually referenced to their respective genomic location, e.g. the UL48 gene encodes a viral transactivator referred to variously as VP16 (Virion Protein 16), αTIF (α gene Trans-Inducing Factor), ICP25 (Infected Cell Protein 25) or VMW65 (Virion Molecular Weight 65 kDa). A complete description of the HSV-1 genome, genes, coding regions, and function of viral proteins can now be found at www.stdgen.lanl.gov.

Section snippets

Overview

The general pattern of HSV gene expression in productively infected cells was first described over 20 years ago (for review, see Roizman and Sears, 1996). Extensive investigations since that time have revealed layers of complexity to the pattern, but the overall picture as first portrayed remains remarkably the same. The scheme of viral gene expression that was established revealed that three groups of virus-specific polypeptides, designated as α (immediate-early, IE), β (early) and γ (late),

Overview

In vivo, HSV replicates primarily in two very distinct cell types: epithelial cells at the site of initial infection, and post-mitotic sensory neurons that innervate that site. It is reasonable to assume that the virus has evolved specific functions to facilitate productive reproduction in these two distinctive milieu. While it is obvious that productive infection has a profound effect on these cells, the unique characteristics of each cell type undoubtedly exert a substantial influence on the

Conclusions and perspectives

The last few years have witnessed several amazing advancements in our understanding of the regulation of HSV gene expression. Taken together, these findings reveal intricacies of gene regulation that were unimaginable when the general scheme of viral gene expression was first described over 20 years ago. As several of the examples cited in this brief review illustrate, the virus has evolved various mechanisms to regulate the orderly and efficient expression of its genetic program. These

Note added in proof

The newest edition of Fields Virology, which contain updated reviews of herpes simplex virus and other herpes viruses, is now in press (Fields Virology, 4th Edition. Knipe, D.M., Howley, P.M. (Eds.), Lippincott Williams & Wilkins, Philadelphia, PA).

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