Enhanced in vitro Reactivation of Herpes Simplex Virus Type 2 from Latently Infected Guinea-pig Neural Tissues by 5-Azacytidine

Stephanopoulos, Dimitrios E.; Kappes, John C.; Bernstein, David I.

doi:10.1099/0022-1317-69-5-1079

Cited by 18 publications

(12 citation statements)

References 32 publications

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“…Detection of latent virus from additional animals might have been enhanced by incorporation of demethylating agents in the culture medium (Stephanopoulos et al, 1988) or by hybridization techniques (Stanberry et al, 1985 b). We and others have previously reported that HSV may also establish a latent infection in guinea-pig genital skin (Stanberry et al, 1985b;Bernstein & Kappes, 1988).…”

Section: Discussionmentioning

confidence: 99%

Preinfection Prophylaxis with Herpes Simplex Virus Glycoprotein Immunogens: Factors Influencing Efficacy

Stanberry¹,

Myers²,

Stephanopoulos³

et al. 1989

Journal of General Virology

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SUMMARYUsing a guinea-pig model of genital herpes simplex virus (HSV) infection we explored the protection afforded by preinfection immunization with HSV glycoproteins. Glycoprotein immunogens prepared by recombinant DNA technology were found to be as effective as immunogens purified from HSV-infected cell cultures. Immunized animals developed less severe primary disease and also experienced less frequent recurrent infections. Protection was influenced by both adjuvant and route of administration. These studies suggest that recombinant HSV glycoproteins may be effective immunogens for human clinical trials, but that the development of an effective vaccine will require identification of new potent adjuvants that are safe for human use.

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Section: Discussionmentioning

confidence: 99%

Preinfection Prophylaxis with Herpes Simplex Virus Glycoprotein Immunogens: Factors Influencing Efficacy

Stanberry¹,

Myers²,

Stephanopoulos³

et al. 1989

Journal of General Virology

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“…Youssoufian et al demonstrated that a latent infection of chicken lymphocytes with HSV-1 was associated with DNA methylation and that virus could be induced to reactivate in this in vitro system following treatment of the lymphocytes with 5-azacytidine, an inhibitor of DNA methyltransferase (36). Two other studies demonstrated that use of methyltransferase inhibitors enhanced the reactivation of HSV-2 from latently infected guinea pig ganglia (5,30). While Dressler and Fraser showed that the HSV-1 genome was not extensively methylated during latency (13), the possibility remained that DNA methylation at discrete sites in the promoters of key regulatory genes could play a role in the regulation of latent transcription.…”

Section: Vol 78 2004 Histone Modifications and Hsv-1 Latent Gene Exmentioning

confidence: 99%

Specific Histone Tail Modification and Not DNA Methylation Is a Determinant of Herpes Simplex Virus Type 1 Latent Gene Expression

Kubat

Tran

McAnany

et al. 2004

J Virol

154

160

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During herpes simplex virus type 1 (HSV-1) latency, gene expression is tightly repressed except for the latency-associated transcript (LAT). The mechanistic basis for this repression is unknown, but its global nature suggests regulation by an epigenetic mechanism such as DNA methylation. Previous work demonstrated that latent HSV-1 genomes are not extensively methylated, but these studies lacked the resolution to examine methylation of individual CpGs that could repress transcription from individual promoters during latency. To address this point, we employed established models to predict genomic regions with the highest probability of being methylated and, using bisulfite sequencing, analyzed the methylation profiles of these regions. We found no significant methylation of latent DNA isolated from mouse dorsal root ganglia in any of the regions examined, including the ICP4 and LAT promoters. This analysis indicates that methylation is unlikely to play a major role in regulating HSV-1 latent gene expression. Subsequently we focused on differential histone modification as another epigenetic mechanism that could regulate latent transcription. Chromatin immunoprecipitation analysis of the latent HSV-1 DNA repeat regions demonstrated that a portion of the LAT region is associated with histone H3 acetylated at lysines 9 and 14, consistent with a euchromatic and nonrepressed structure. In contrast, the chromatin associated with the HSV-1 DNA polymerase gene located in the unique long segment was not enriched in H3 acetylated at lysines 9 and 14, suggesting a transcriptionally inactive structure. These data suggest that histone composition may be a major regulatory determinant of HSV latency.

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“…The effects of HMBA and DMSO in these systems have been attributed to demethylation, for two reasons. First, addition of 5-azacytidine or L-ethionine also improves reactivation of latent HSV (Whitby et al, 1987;Stephanopoulos et al, 1988), and second, during induction of erythroleukaemic cells, a transient decrease in 5-methylcytosine levels occurs (Razin et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Hexamethylene bisacetamide stimulates herpes simplex virus immediate early gene expression in the absence of trans-induction by Vmw65

McFarlane

Daksis²,

Preston³

1992

Journal of General Virology

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Hexamethylene bisacetamide (HMBA) and DMSO are known to induce differentiation of cultured erythroleukaemic cells and to enhance the reactivation of latent herpes simplex virus (HSV) after explantation of ganglia. We report that the presence of these compounds in cell culture medium overcomes the replication defect of in1814, an HSV-1 mutant with an insertion mutation that inactivates the virion transinducing factor, Vmw65 (VP16). The effect of HMBA was not cell type-specific and was attained even by a short exposure (1-5 to 5 h) to the agent early after infection. The presence of HMBA resulted in an increase in immediate early (IE) RNA accumulation after infection of cells in the presence of cycloheximide, such that RNA levels in inl814-infected cells approached the values observed in wild-type HSV-1-infected cells in the absence of HMBA. Transport of viral DNA to the cell nucleus was not affected by HMBA. The results suggest that HMBA-and DMSOmediated enhancement of reactivation from latency is due to an increase in IE RNA production. In addition, these studies demonstrate a primary effect of HMBA on gene regulation which may bea paradigm for initial events during erythroleukaemic cell differentiation.

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Enhanced in vitro Reactivation of Herpes Simplex Virus Type 2 from Latently Infected Guinea-pig Neural Tissues by 5-Azacytidine

Cited by 18 publications

References 32 publications

Preinfection Prophylaxis with Herpes Simplex Virus Glycoprotein Immunogens: Factors Influencing Efficacy

Preinfection Prophylaxis with Herpes Simplex Virus Glycoprotein Immunogens: Factors Influencing Efficacy

Specific Histone Tail Modification and Not DNA Methylation Is a Determinant of Herpes Simplex Virus Type 1 Latent Gene Expression

Hexamethylene bisacetamide stimulates herpes simplex virus immediate early gene expression in the absence of trans-induction by Vmw65

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