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ICP0 inhibits the decrease of HSV amplicon-mediated transgene expression.

ABSTRACT: The herpes simplex virus (HSV) amplicon vector produces an initial host response that limits transgene expression. In this study, we hypothesized that restoration of the HSV gene infected cell protein (ICP0) into the amplicon could circumvent this host response and thus overcome silencing of encoded transgenes. To test this, we constructed an amplicon vector that encodes the ICP0 under control of its native promoter (ICP0+ amplicon). Expression of ICP0 was transient and, at a multiplicity of infection (MOI) of 1, did not significantly alter interferon (IFN)-based responses against the vector or cell kinetics/apoptosis of infected cells. Chromatin immunoprecipitation (ChIP) PCR analysis revealed that conventional amplicon DNA became associated with histone deacetylase 1 (HDAC1) immediately after infection, whereas ICP0+ amplicon DNA remained relatively unbound by HDAC1 for at least 72 hours after infection. Mice administered systemic ICP0+ amplicon exhibited significantly greater and more sustained transgene expression in their livers than did those receiving conventional amplicon, likely due to increased transcriptional or post-transcriptional activity rather than increased copy numbers of vector DNA. These findings indicate that restoration of ICP0 expression may be employed within HSV amplicon constructs to decrease transgene silencing in vitro and in vivo.

SUBMITTER: Suzuki M

PROVIDER: S-EPMC2835108 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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ICP0 inhibits the decrease of HSV amplicon-mediated transgene expression.

Suzuki Masataka M Kasai Kazue K Ohtsuki Akihiro A Godlewski Jakub J Nowicki Michal O MO Chiocca E Antonio EA Saeki Yoshinaga Y

Molecular therapy : the journal of the American Society of Gene Therapy 20090217 4

The herpes simplex virus (HSV) amplicon vector produces an initial host response that limits transgene expression. In this study, we hypothesized that restoration of the HSV gene infected cell protein (ICP0) into the amplicon could circumvent this host response and thus overcome silencing of encoded transgenes. To test this, we constructed an amplicon vector that encodes the ICP0 under control of its native promoter (ICP0+ amplicon). Expression of ICP0 was transient and, at a multiplicity of inf ...[more]

PMID: 19223864

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Project description:BackgroundHerpes simplex virus-1 (HSV-1) infections of the central nervous system (CNS) can result in HSV-1 encephalitis (HSE) which is characterized by severe brain damage and long-term disabilities. Different cell types including neurons and astrocytes become infected in the course of an HSE which leads to an activation of glial cells. Activated glial cells change their neurotrophic factor profile and modulate inflammation and repair. The superfamily of fibroblast growth factors (FGFs) is one of the largest family of neurotrophic factors comprising 22 ligands. FGFs induce pro-survival signaling in neurons and an anti-inflammatory answer in glial cells thereby providing a coordinated tissue response which favors repair over inflammation. Here, we hypothesize that FGF expression is altered in HSV-1-infected CNS cells.MethodWe employed primary murine cortical cultures comprising a mixed cell population of astrocytes, neurons, microglia, and oligodendrocytes. Astrocyte reactivity was morphometrically monitored by an automated image analysis algorithm as well as by analyses of A1/A2 marker expression. Altered FGF expression was detected by quantitative real-time PCR and its paracrine FGF activity. In addition, HSV-1 mutants were employed to characterize viral factors important for FGF responses of infected host cells.ResultsAstrocytes in HSV-1-infected cortical cultures were transiently activated and became hypertrophic and expressed both A1- and A2-markers. Consistently, a number of FGFs were transiently upregulated inducing paracrine neurotrophic signaling in neighboring cells. Most prominently, FGF-4, FGF-8, FGF-9, and FGF-15 became upregulated in a switch-on like mechanism. This effect was specific for CNS cells and for a fully functional HSV-1. Moreover, the viral protein ICP0 critically mediated the FGF switch-on mechanism.ConclusionsHSV-1 uses the viral protein ICP0 for the induction of FGF-expression in CNS cells. Thus, we propose that HSV-1 triggers FGF activity in the CNS for a modulation of tissue response upon infection.

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ICP0 inhibits the decrease of HSV amplicon-mediated transgene expression.

Publications

ICP0 inhibits the decrease of HSV amplicon-mediated transgene expression.

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