Potential role for herpes simplex virus ICP8 DNA replication protein in stimulation of late gene expression

Gao, Min; Knipe, David M.

doi:10.1128/jvi.65.5.2666-2675.1991

Cited by 94 publications

(51 citation statements)

References 44 publications

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“…HSV-1infected cells were identified by the expression of the viral protein, ICP8; HSV-1 ICP8 is a single-stranded DNA-binding protein that is also required for HSV DNA synthesis and enhances late gene transcription. 23 ICP8 accumulates with ICP4, the immediate early protein, ICP27 and virion capsid proteins in replication compartments and has been shown to interact with cellular proteins found in these compartments, based on coimmunoprecipitation. 24 MxA exhibited nuclear localization in fibroblasts that were infected with HSV-1, in contrast to its strictly cytoplasmic distribution when induced with IFN-a ( Figure 2a).…”

Section: Mxa Is Expressed In Hsv-1-infected Cells and Exhibits Alterementioning

confidence: 99%

Herpes simplex virus‐1 induces expression of a novel MxA isoform that enhances viral replication

Che

Reichelt

et al. 2010

Immunol Cell Biol

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MxA is an antiviral protein induced by interferon (IFN)-α/β that is known to inhibit the replication of many RNA viruses. In these experiments, the 76-kDa MxA protein expressed in IFN-α-treated cells was shown to have antiviral activity against herpes simplex virus-1 (HSV-1), a human DNA virus. However, MxA was expressed as a 56-kDa protein in HSV-1-infected cells in the absence of IFN-α. This previously unrecognized MxA isoform was produced from an alternatively spliced MxA transcript that had a deletion of Exons 14–16 and a frame shift altering the C-terminus. The variant MxA (varMxA) isoform was associated with HSV-1 regulatory proteins and virions in nuclear replication compartments. varMxA expression enhanced HSV-1 infection as shown by a reduction in infectious virus titers from cells in which MxA had been inhibited by RNA interference and by an increase in HSV-1 titers when the 56-kDa varMxA was expressed constitutively. Thus, the human MxA gene encodes two MxA isoforms, which are expressed differentially depending on whether the stimulus is IFN-α or HSV-1. These findings show that alternative splicing of cellular mRNA can result in expression of a novel isoform of a host defense gene that supports instead of restricting viral infection.

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Section: Mxa Is Expressed In Hsv-1-infected Cells and Exhibits Alterementioning

confidence: 99%

Herpes simplex virus‐1 induces expression of a novel MxA isoform that enhances viral replication

Che

Reichelt

et al. 2010

Immunol Cell Biol

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“…It is required for DNA replication as a single-stranded DNA (ssDNA) binding protein and plays a role in the initiation of DNA replication in conjunction with the origin binding protein UL9 (36)(37)(38)(39)(40). It also has a separate role in the initiation of late gene expression (41,42) and is thought to be important for viral recombination (43). Interestingly, ICP8 is also known to contain an RNase H-like domain homologous to that of HIV integrase (35).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to its known roles in DNA replication, ICP8 also independently stimulates transcription of at least three late genes, the glycoprotein C (gC), glycoprotein D (gD), and UL47 genes (41,42). To determine the effects of raltegravir on FeHV-1 gene expression, we adopted a methodology similar to that used to originally define the effects of ICP8 on late gene expression (41,42). To this end, cells were infected at a high multiplicity of infection (MOI), treated with raltegravir, and collected at 6 hpi for quantitative reverse transcription (qRT)-PCR analysis.…”

Section: Resultsmentioning

confidence: 99%

“…6B). To determine if the downregulation of late genes was (i) a direct consequence of the reduction in DNA replication, as expression of late genes is known to be partially dependent on DNA replication (46), or (ii) an independent effect on late gene expression specifically, we repeated the experiment using PAA instead of raltegravir, an approach that was used previously to define the roles of ICP8 during HHV-1 replication (41,42). When treating infected cells with PAA, using a concentration that we previously determined resulted in a level of inhibition of FeHV-1 genome replication similar to that of raltegravir (47), we did not observe downregulation of any of the tested genes ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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The HIV Integrase Inhibitor Raltegravir Inhibits Felid Alphaherpesvirus 1 Replication by Targeting both DNA Replication and Late Gene Expression

Pennington

Voorhees

Callaway

et al. 2018

J Virol

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Alphaherpesvirus-associated ocular infections in humans, caused by human alphaherpesvirus 1 (HHV-1), remain challenging to treat due to the frequency of drug application required and the potential for the selection of drug resistant viruses. Repurposing on-the-market drugs is a viable strategy to accelerate the pace of drug development. It has been reported that the human immunodeficiency virus (HIV) integrase inhibitor raltegravir inhibits HHV-1 replication by targeting the DNA polymerase accessory factor and limits terminase-mediated genome cleavage of the human betaherpesvirus 5 (HHV-5). We have previously shown, both and that raltegravir can also inhibit the replication of felid alphaherpesvirus 1 (FeHV-1), a common ocular pathogen of cats with a similar pathogenesis to HHV-1 ocular disease. In contrast to what was reported for HHV-1, we were unable to select for a raltegravir-resistant FeHV-1 in order to define any basis for drug action. A candidate-based approach to explore the mode-of-action of raltegravir against FeHV-1 showed that raltegravir did not impact FeHV-1 terminase function, as described for HHV-5. Instead, raltegravir inhibited DNA replication, similar to HHV-1, but by targeting the initiation of viral DNA replication rather than elongation. In addition, we found that raltegravir specifically repressed late gene expression independent of DNA replication, and both activities are consistent with inhibition of ICP8. Taken together, these results suggest that raltegravir could be a valuable therapeutic agent against herpesviruses. The rise of drug-resistant herpesviruses is a long-standing concern, particularly among immunocompromised patients. Therefore, therapies targeting viral proteins other than the DNA polymerase that may be less likely to lead to drug-resistant viruses are urgently needed. Using FeHV-1, an alphaherpesvirus closely related to HHV-1 that similarly causes ocular herpes in its natural host, we found that the HIV integrase inhibitor raltegravir targets different stages of the virus life cycle beyond DNA replication and that it does so without developing drug resistance under the conditions tested. This shows that this drug could prove a viable strategy for the treatment of herpesvirus infections.

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“…The aim of the present study was therefore to obtain results on the immune response against two HSV-1 gene products known to be essential in viral replication, namely ICP8 and VP16. ICP8 is a multifunctional ss DNA binding protein involved in both DNA replication and gene regulation [Gao and Knipe, 1991;Lee and Knipe, 1985]. VP16 (otherwise known as Vmw65 or ␣-TIF) is a major tegument protein of 65 kD essential for the transcriptional activation of viral IE genes [Batterson and Roizman, 1983].…”

Section: Introductionmentioning

confidence: 99%

Immune response to the herpes simplex type 1 regulatory proteins ICP8 and VP16 in infected persons

Spatz

Wolf²,

Thon

et al. 2000

J. Med. Virol.

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The specific immune responses directed against the viral single stranded (ss) DNA binding protein ICP8 and the transactivator of immediate early (IE) gene expression VP16 (alpha-trans inducing factor, Vmw65) in HSV type 1 seropositive humans were examined. The results described in this paper indicate that neither ICP8 nor VP16 were able to induce a recall response in lymphocytes of healthy HSV seropositive individuals without recurrent infection, although CD4+ T cells purified from these individuals responded to both viral proteins in vitro when monocyte derived dendritic cells were used as antigen presenting cells. A recall response, however, could be induced to both viral proteins in T cells of patients with recurrent HSV infections when blood monocytes were used. Moreover, ICP8- and VP16-specific antibodies could be detected in the serum of patients with recurrent HSV infections whereas, in contrast, these antibodies were virtually absent in healthy HSV seropositive individuals without recurrences. These data represent the first systematic study of the immunological properties of ICP8 in humans, indicating a significant difference in the response to the essential viral regulators ICP8 and VP16 in HSV-1 seropositive healthy individuals as opposed to patients with recurrent HSV-1 infections.

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Potential role for herpes simplex virus ICP8 DNA replication protein in stimulation of late gene expression

Cited by 94 publications

References 44 publications

Herpes simplex virus‐1 induces expression of a novel MxA isoform that enhances viral replication

Herpes simplex virus‐1 induces expression of a novel MxA isoform that enhances viral replication

The HIV Integrase Inhibitor Raltegravir Inhibits Felid Alphaherpesvirus 1 Replication by Targeting both DNA Replication and Late Gene Expression

Immune response to the herpes simplex type 1 regulatory proteins ICP8 and VP16 in infected persons

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