ENTRY OF HERPES SIMPLEX VIRUS INTO CELLS

该项目的最终目标是通过以下方式确定机制： 单纯疱疹病毒（HSV）侵入人体细胞， 感染 HSV的两种血清型之一或两者感染大多数 所有人类群体的人，是一系列的原因， 疾病（复发性口腔和生殖器病变，严重的播散性 新生儿疾病，脑炎和失明导致的 角膜感染）。了解HSV感染的不同途径 感染不同类型的人体细胞， 阻止病毒进入细胞的抗病毒药物， HSV活疫苗可能诱导免疫而不感染关键的 细胞，如神经系统的细胞。 支持的研究 格兰特已经导致了几种细胞表面蛋白质的鉴定 作为细胞表面糖胺聚糖（GAG）的共受体， 介导HSV-1、HSV-2和两种动物α疱疹病毒的进入 [伪狂犬病病毒（PRV）和牛疱疹病毒1（BHV-1）]进入人体 细胞 不同的人类细胞类型表达不同的共- 受体，其中任何一种似乎都足以与GAG， 中介进入 共受体的HSV配体显示为gD 在至少两个案例中。 下一个时期的具体目标和办法 包括：（1）使用工程化的杂合蛋白来鉴定 三种相关共受体（HveB、HveC和Pvr）的结构域， HveD）负责它们与HveD的不同的进入活动光谱。 （2）使用HSV突变体鉴定上述病毒; 由每种蛋白共同介导的病毒进入所需的HSV糖蛋白 受体，鉴于初步迹象表明，病毒的要求， 进入依赖于由细胞表达的蛋白质辅助受体;（3）使用 检测mRNA和蛋白质的分子方法， HSV进入的人共受体在各种人中的表达水平 细胞和组织以及用于进入的辅助受体的鉴定 在选定的培养人类细胞类型中。获得的结果应 定义HSV-1或HSV-2进入各种人类的决定因素， 细胞类型以及病毒株和细胞易感性 来控制人类感染的传播。

The ultimate objective of this project is to define the mechanisms by which herpes simplex viruses (HSV) invade human cells to establish infection. One or both of the two serotypes of HSV infect a majority of people in all human populations and are the cause of a spectrum of diseases (recurrent oral and genital lesions, severe disseminated disease in newborn infants, encephalitis, and blindness resulting from corneal infection). Understanding the different pathways by which HSV infects different types of human cells can lead to new types of antiviral drugs that block virus entry into cells and to the design of HSV live vaccines that might induce immunity without infecting critical cells such as those of the nervous system. Studies supported by this grant have led to the identification of several cell surface proteins that serve as coreceptors with cell surface glycosaminoglycans (GAG) to mediate the entry of HSV-1, HSV-2 and two animal alphaherpesviruses [pseudorabies virus (PRV) and bovine herpesvirus 1 (BHV-1)] into human cells. Different human cell types express different subsets of the co- receptors, any one of which appears to be sufficient with GAGs to mediate entry. An HSV ligand for the co-receptors was shown to be gD in at least two cases. Specific aims and approaches for the next period include: (1) use of engineered hybrid proteins for identification of the structural domains of three related co-receptors (HveB, HveC and Pvr- HveD) responsible for their different spectra of entry activity with the viruses listed above; (2) use of HSV mutants for identification of the HSV glycoproteins required for viral entry mediated by each protein co- receptor, given preliminary indications that viral requirements for entry depend on the protein co-receptor expressed by the cell; (3) use of molecular methods to detect mRNA and protein for assessment of the expression levels of human co-receptors for HSV entry in various human cells and tissues and identification of the coreceptors used for entry in selected cultured human cell types. The results obtained should define the determinants for entry of HSV-1 or HSV-2 into various human cell types and the extent to which virus strain and cell susceptibility to entry govern spread of infections in human beings.