Herpes Simplex VIrus Disease of Female Genital Tract

女性生殖道单纯疱疹病毒病

• 批准号: 6842443
• 负责人: PATRICIA G SPEAR
• 金额: $ 27.14万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6842443
• 关键词: antiviral agents; cell adhesion molecules; communicable disease control; communicable disease transmission; complement; cooperative study; disease /disorder etiology; gene mutation; genetically modified animals; genital herpes; heparan sulfate; herpes simplex virus 2; host organism interaction; human tissue; immunocytochemistry; laboratory mouse; reporter genes; spinal ganglion; tissue /cell culture; topical drug application; virus envelope; virus genetics; virus receptors; women' s health

Herpes simplex virus (HSV) is a major cause of sexually transmitted disease. The disease can be controlled to some extent with antiviral drugs but not yet prevented or cured. The overall goal of this project is to define the molecular interactions required for HSV to infect cells of the female genital tract and to spread to cells of the nervous system, with a focus on viral ligands and cell receptors that mediate HSV type 2 (HSV-2) entry into human and mouse cells. Besides heparan sulfate, which can serve as a binding receptor for virus, the two most efficient entry receptors for HSV-2 are HVEM and nectin-1, both for mice and for humans. Thus, receptor-dependent aspects of pathogenesis in mice are likely to be relevant to humans. The ligands for heparan sulfate are viral gB and gC, the latter of which also binds the C3b component of complement and protects virus from neutralization by complement. Viral gD is the ligand for HVEM and nectin-1. It is our hypothesis that HSV uses different receptors to enter different cell types and that inability of the virus (due to mutation or natural polymorphism) to use a particular entry receptor can either prevent infection or change the course of disease. This hypothesis will be tested in a mouse model of disease resulting from virus inoculation via the vagina and in primary cells cultured from the mouse and human female genital tracts. The specific aims are to determine (1) whether the disease course in mice and spectrum of cells infected are altered by mutations of the mice that abrogate HVEM or nectin-1 expression or by mutations in HSV-2 that prevent viral entry via HVEM or nectin-1 or that alter interactions with heparan sulfate and complement; (2) whether mice that survive infection with an attenuated HSV-2 mutant escape latent infection but exhibit resistance to challenge with wild-type HSV-2 and (3) whether the HSV-2 mutants have altered ability to infect cells cultured from the female genital tracts of mice and humans and whether complement influences viral infectivity. This project focuses on the central theme of the center, namely acquisition, pathogenesis and prevention of STIs in women. Results obtained will identify interactions that must be blocked to prevent HSV infect on and will address the feasibility of a non-neurotropic live HSV vaccine.

单纯疱疹病毒（HSV）是性传播疾病的主要原因。该疾病可以在某种程度上通过抗病毒药物来控制，但尚未阻止或治愈。该项目的总体目标是定义HSV感染女性生殖道细胞并扩散到神经系统细胞所需的分子相互作用，重点是介导HSV 2型（HSV-2）进入人类和小鼠细胞的病毒配体和细胞受体。除了可以用作病毒的结合受体的硫酸乙酰肝素外，HSV-2的两个最有效的入口受体是HVEM和Nectin-1，包括小鼠和人类。因此，小鼠发病机理的受体依赖方面可能与人有关。硫酸乙酰肝素的配体是病毒GB和GC，后者也结合了补体的C3B成分， 通过补体保护病毒免受中和。病毒GD是HVEM和Nectin-1的配体。我们的假设是，HSV使用不同的受体进入不同的细胞类型，并且病毒（由于突变或自然多态性引起的）使用特定的入口受体可以防止感染或改变疾病的病程。该假设将在通过阴道接种病毒和从小鼠和人类雌性生殖道培养的原代细胞引起的疾病模型中进行检验。具体的目的是确定（1）通过消除HVEM或Nectin-1表达的小鼠的突变，还是通过HSV-2突变的HSV-2突变改变了感染的小鼠和感染细胞的疾病病程，以防止通过HVEM或Nectin-1进入病毒的病毒性或与乙酰肝素硫酸盐和补体的相互作用。 （2） 是否通过衰减的HSV-2突变体逃脱潜在感染而感染感染的小鼠是否表现出抗野生型HSV-2挑战的耐药性和（3）（3）HSV-2突变体是否改变了从小鼠和人类生殖器培养的细胞中感染细胞的能力，以及补体影响病毒感染力。该项目着重于该中心的中心主题，即妇女的性传播感染，发病机理和预防性传播感染。获得的结果将确定必须阻止的相互作用，以防止HSV感染，并将解决非神经性实时HSV疫苗的可行性。