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Viral And host mechanisms that tilt the HSV lytic/latent balance

导致 HSV 裂解/潜伏平衡倾斜的病毒和宿主机制

基本信息

批准号：
9102872
负责人：
DONALD M COEN
金额：
$ 177.52万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-02 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9102872
关键词：
Acute Affect Animals Antiviral Agents Area Autophagocytosis Back Biological Assay Chromatin Chromatin Structure Complex Cultured Cells DNA Sequence Disease Drug Targeting Enzymes Equilibrium Gene Expression Genes Genital system Genome Growth HIV Infections Herpesvirus 1 Histones Immune response In Vitro Infection Investigation Laboratories Latent Virus Latent virus infection phase Life Lytic Lytic Phase Maintenance MicroRNAs Morbidity - disease rate Mus Mutate Natural Immunity Neurons Pharmaceutical Preparations Proteins RNA Recruitment Activity Recurrence Research Risk Role Sensory Ganglia Simplexvirus Site Structure of trigeminal ganglion System Testing Transcript Untranslated RNA Viral Viral Genes Viral Genome Viral Physiology Viral Proteins Virus Virus Latency Work chromatin remodeling combat combinatorial genital herpes histone modification in vivo latency associated transcript latent infection lytic gene expression mortality mucosal site mutant nervous system disorder programs promoter response therapeutic target viral DNA

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex viruses cause considerable morbidity and mortality. They undergo a lytic, productive infection at the mucosal sites and spread into sensory ganglia, where they undergo a latent infection for the life of the host. Reactivation leads to recurrent infection and disease. Antiviral drugs have been defined that inhibit the lytic infection cycle, but there are no approaches that target the latent virus. We have defined the role of viral gene products such as LAT and ICPO in modulating the chromatin structure during lytic and latent infection, but further basic information is needed about these mechanisms for discovery of therapeutics that target HSV latent infection. In this application our specific aims are: a. To test hypotheses for possible mechanisms by which the HSV latency-associated transcript reduces lytic gene expression during acute infection and during latent infection of trigeminal ganglia: LAT acts as a long noncoding RNA that recruits histone-modifying complexes to the viral genome, b. LAT leads to chromatin changes by serving as a precursor to an miRNA that reduces ICPO expression through studies of miRNA mutant viruses (with Coen lab), c. LAT regulatory DNA sequences act in a cis-acting manner to promote chromatin on the viral lytic genes, d. LAT leads to differential targeting of the viral genome through studies of genome targeting in cultured neurons with the Leib lab. 2. To define the mechanisms by which the HSV ICPO protein regulates chromatin structure during acute infection and latent infection of trigeminal ganglia. We have exciting unpublished results that ICPO mutant viruses have a different chromatin profile on their genome during latent infection. We will test the hypothesis that ICPO acts to alter the chromatin state by recruiting histone modification enzymes to viral and cellular genes. 3. To define Interactions between LAT and ICPO in regulating HSV chromatin. We will test the hypothesis that LAT forms duplex RNA with ICPO transcripts to recruit histone modifying enzymes by mutating the ICPO promoter or mutating the ICPO translational initiation site and by constructing LAT and ICPO double mutant viruses to determine their combinatorial effects on latent infection, and viral chromatin. RELEVANCE: Herpes simplex viruses cause considerable genital, ocular and nervous system disease, and genital herpes increases the risk of HIV infection. There are drugs that target the active growth of herpes simplex virus but none that target the latent infection. This research wil define basic mechanisms of herpes simplex virus latent infection and new targets for potential drugs to treat the latent infection of these viruses. Project 1: Chromatin and the lytic/latent balance Project Leader (PL): Knipe, David M. DESCRIPTION (provided by applicant): Herpes simplex viruses cause considerable morbidity and mortality. They undergo a lytic, productive infection at the mucosal sites and spread into sensory ganglia, where they undergo a latent infection for the life of the host. Reactivation leads to recurrent infection and disease. Antiviral drugs have been defined that inhibit the lytic infection cycle, but there are no approaches that target the latent virus. We have defined the role of viral gene products such as LAT and ICP0 in modulating the chromatin structure during lytic and latent infection, but further basic information is needed about these mechanisms for discovery of therapeutics that target HSV latent infection. In this application our specific aims are: a. To test hypotheses for possible mechanisms by which the HSV latency-associated transcript reduces lytic gene expression during acute infection and during latent infection of trigeminal ganglia: LAT acts as a long noncoding RNA that recruits histone-modifying complexes to the viral genome. b. LAT leads to chromatin changes by serving as a precursor to an miRNA that reduces ICP0 expression through studies of miRNA mutant viruses (with Coen lab). c. LAT regulatory DNA sequences act in a cis-acting manner to promote chromatin on the viral lytic genes. d. LAT leads to differential targeting of the viral genome through studies of genome targeting in cultured neurons with the Leib lab. 2. To define the mechanisms by which the HSV ICP0 protein regulates chromatin structure during acute infection and latent infection of trigeminal ganglia. We have exciting unpublished results that ICP0 mutant viruses have a different chromatin profile on their genome during latent infection. We will test the hypothesis that ICP0 acts to alter the chromatin state by recruiting histone modification enzymes to viral and cellular genes. 3. To define Interactions between LAT and ICP0 in regulating HSV chromatin. We will test the hypothesis that LAT forms duplex RNA ICP0 transcripts to recruit histone modifying enzymes by mutating the ICP0 promoter or mutating the ICP0 translational initiation site and by constructing LAT and ICP0 double mutant viruses to determine their combinatorial effects on latent infection, and viral chromatin. RELEVANCE: Herpes simplex viruses cause considerable genital, ocular, and nervous system disease, and genital herpes increases the risk of HIV infection. There are drugs that target the active growth of herpes simplex virus but none that target the latent infection. This research wil define basic mechanisms of herpes simplex virus latent infection and new targets for potential drugs to treat the latent infection of these viruses.

描述（由申请人提供）：单纯疱疹病毒引起相当高的发病率和死亡率。它们在粘膜部位发生溶解性、生产性感染，并扩散到感觉神经节，在那里它们经历潜伏感染，直至宿主的一生。重新激活导致