ReviewRegulation of herpes simplex virus gene expression
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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2019, Journal of Controlled ReleaseCitation Excerpt :Read-out of infection was performed after a period of time that corresponds to ca. 2 replication cycles of the virus via quantification of the β-galactosidase activity using a sensitive chemiluminescence based assay. This common model of HSV-2 infectivity is characterized by an early expression of β-galactosidase (as early as 6 h post-infection with HSV [38]) and a relatively late expression of the viral thymidine kinase [39–41], the latter being necessary to phosphorylate acyclovir and to observe the associated antiviral effects. [42] This means that inhibition of HSV-2 infectivity is only complete for inhibitors of viral cell entry such as heparin [43] whereas intracellular ACV that acts at a later stage of the viral replication cycle is expected to exert pronounced but not exhaustive decrease of viral infectivity.
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2017, Journal of Biological ChemistryHuman antiviral protein IFIX suppresses viral gene expression during herpes simplex virus 1 (HSV-1) infection and is counteracted by virus-induced proteasomal degradation
2017, Molecular and Cellular ProteomicsCitation Excerpt :Next, we compared the relative levels of viral genes after infection of either IFIX-GFP or EGFP control cells. Given the known temporal cascade of viral gene expression upon HSV-1 infection (40, 41), we monitored immediate-early and early viral genes. We found IFIX-dependent decreased levels of both the immediate-early viral gene ICP27 and the early viral gene ICP8 (Fig. 7B).