Herpes Simplex VIrus Disease of Female Genital Tract

单纯疱疹病毒(HSV)是性传播疾病的主要原因。这种疾病可以通过抗病毒药物在一定程度上得到控制，但尚未预防或治愈。该项目的总体目标是确定单纯疱疹病毒感染女性生殖道细胞并传播到神经系统细胞所需的分子相互作用，重点是介导2型单纯疱疹病毒(HSV-2)进入人类和小鼠细胞的病毒配体和细胞受体。除了可以作为病毒结合受体的硫酸肝素外，HSV-2的两个最有效的进入受体是HVEM和Nectin-1，对小鼠和人类都是如此。因此，小鼠发病机制中依赖受体的方面可能与人类有关。硫酸乙酰肝素的配体是病毒gB和GC，后者还与补体和 通过补体保护病毒免受中和。病毒gD是HIV和Nectin-1的配体。我们的假设是，单纯疱疹病毒使用不同的受体进入不同的细胞类型，病毒(由于突变或自然多态)无法使用特定的进入受体可以预防感染或改变病程。这一假说将在通过阴道接种病毒引起的小鼠疾病模型以及从小鼠和人类女性生殖道培养的原代细胞中得到验证。其具体目的是确定(1)小鼠的病程和受感染细胞的谱是否因小鼠的突变而改变，这些突变使Hvem或Nectin-1的表达丧失，或者由于HSV-2的突变而阻止病毒通过Hvem或Nectin-1进入，或者改变与硫酸肝素和补体的相互作用；(2) (3)HSV-2突变株是否改变了感染小鼠和人类女性生殖道培养细胞的能力，以及补体是否影响病毒的感染性。该项目侧重于该中心的中心主题，即妇女性传播感染的获取、发病机制和预防。所获得的结果将确定必须阻止的相互作用，以防止HSV感染，并将解决非嗜神经性HSV活疫苗的可行性。

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.