VIRAL AND CELL DETERMINANTS OF HSV DISEASE

本文所述研究的最终目的是确定1型和2型单纯疱疹病毒（HSV- 1和HSV-2）进入生殖道细胞以及感染从入口传播到其他组织（特别是神经系统）的病毒和细胞要求。通过阴道途径接种的小鼠将提供疾病的动物模型。这种感染和疾病的小鼠模型可能提供与人类疾病相关的信息，部分原因是人类和小鼠病毒进入细胞的受体是同源物（由进化相关的基因编码），并且因为人类中由HSV引起的性传播疾病的许多方面与通过阴道途径接种的小鼠中观察到的相似。最近，我们克隆了三个不同的cDNA编码小鼠受体能够介导HSV进入细胞。所有这些都与已知的人类HSV进入受体同源。我们还确定了影响受体使用或病毒在阴道上皮内传播的病毒突变。具体目标是：1）确定迄今为止克隆的三种小鼠受体是否可以解释各种培养的小鼠细胞类型对HSV-1和HSV-2进入的易感性。2)确定改变HSV-1和HSV-2受体使用的病毒突变。3)确定哪些小鼠受体被HSV-1和HSV-2用于进入阴道上皮细胞并扩散到其他细胞类型，包括白细胞和神经系统细胞。这些研究的结果将确定分子鉴定保护阴道上皮和/或神经系统免受感染的新方法。此外，他们可以确定开发更安全的非嗜神经性HSV疫苗株的策略。

The ultimate objective of studies described here is to define viral and cell requirements for the entry of herpes simplex viruses types 1 and 2 (HSV- 1 and HSV-2) into cells of the genital tract and for spread of infection from the portal of entry to other tissues, particularly the nervous system. Mice inoculated via the vaginal route will provide an animal model of disease. This mouse model of infection and disease is likely to provide information relevant to human disease in part because human and mouse cell receptors for viral entry are homologues (encoded by evolutionarily related genes) and because many aspects of sexually transmitted disease caused by HSV in humans are similar to those observed in mice into inoculated via the vaginal route. Recently we cloned three different cDNAs encoding mouse receptors capable of mediating HSV entry into cells. All are homologous to known human receptors for HSV entry. We have also identified viral mutations that influence receptor usage or viral spread within the vaginal epithelium. The specific aims are to: 1) Determine whether the three mouse receptors cloned to date can account for the susceptibility of various cultured mouse cell types to HSV-1 and HSV-2 entry. 2) Identify viral mutations that alter receptor usage by HSV-1 and HSV-2. 3) Determine which mouse receptors are used by HSV-1 and HSV-2for entry into cells of the vaginal epithelium and for spread to other cell types including leukocytes and cells of the nervous system. The results of these studies will define molecular identify new approaches to protection of the vaginal epithelium and/for the nervous system from infection. In addition, they may identify strategies for the development of safer non-neurotropic vaccine strains of HSV.