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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：
10460505
负责人：
DONALD M COEN
金额：
$ 213万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460505
关键词：
Affect Alzheimer&apos s Disease Animal Experiments Animals Antibodies Area Attenuated Vaccines Autophagocytosis Autophagosome Back Behavioral Biogenesis Biological Assay Biology CCCTC-binding factor Chromatin Collaborations Cultured Cells Encephalitis Ensure Equilibrium Experimental Designs Ganglia Gene Expression Genetic Transcription Herpesvirus 1 Heterochromatin Human Immediate-Early Genes Immune Immune response Immunity In Vitro Investigation Keratitis Laboratories Lead Life Lytic Lytic Phase Lytic Virus Maintenance MicroRNAs Mitochondrial Proteins Mus Nervous system structure Neurodegenerative Disorders Neurons Nuclear Export Pathogenesis Play Proteins RNA Regulation Repression Role Series Simplexvirus System Testing Vaccines Viral Viral Genes Viral Genome Viral Proteins Virus Virus Diseases Virus Latency Virus Replication Widespread Disease Work adaptive immune response combat gene product human disease in vitro Model in vivo latency associated transcript latent infection lytic gene expression mutant novel strategies pre-miRNA prevent programs reactivation from latency response statistics viral DNA

项目摘要

Summary/Abstract for Overall Program The long-term objective of this program project is to determine how herpes simplex virus 1 (HSV-1) can switch between a highly active "lytic" infection that produces infectious virus and a more silent latent infection. There are several hypotheses regarding mechanisms that can tilt the balance in favor of lytic infection or latent infection. These mechanisms include viral gene products that affect the chromatin status of the viral genome, post-transcriptional mechanisms that can affect viral and host gene expression, and immune responses and viral gene products that combat those responses. None of these mechanisms is solely responsible for the lytic/latent balance, and each of these mechanisms is highly likely to be connected. For example, immune responses can affect viral gene expression, and post-transcriptional mechanisms can repress the expression of viral gene products that affect chromatin status and combat immune responses. Thus, an integrated approach to the lytic/latent balance is needed. In this Program Project proposal, three senior herpesvirologists with complementary areas of expertise will conduct a series of highly collaborative studies to investigate these mechanisms in three intertwined projects with the aid of three cores. Project 1 will study (including collaborative studies with Project 2) how viral latency- associated transcripts (LATs), the viral protein ICP0, and the host protein CTCF effect a chromatin configuration poised for reactivation during establishment and maintenance of latency in vivo, and with Project 3, in cultured mouse neurons, and in human neurons. Project 2 will focus on how post-transcriptional regulatory mechanisms can repress lytic gene expression and affect chromatin status (with Project 1) and a viral gene product that counteracts immunity (with Projects 3 and 1) and contribute to latency, and a virus block to nuclear export of miRNAs (with Project 1) and the targets of viral miRNAs in cultured cells including mouse and human neurons (Projects 3 and 1). Project 3 will use an in vitro model of latency using cultured neurons from mice, including genetically altered strains, and viral mutants (some from Projects 1 and 2) to test roles of neuron-specific autophagosomes, viral proteins that counter immunity, and antibodies in the nervous system (including those generated by a vaccine from Project 1) in control of viral replication, latency, reactivation, and, gene expression.

整体方案摘要/摘要