ENTRY OF HERPES SIMPLEX VIRUS INTO CELLS

该项目的最终目标是通过以下方式定义机制 哪些单纯疱疹病毒(HSV)入侵人类细胞建立 感染。大多数人感染两种血清型中的一种或两种 在所有人类人口中，是一系列疾病的起因 疾病(复发性口腔和生殖器损害，严重播散 新生儿疾病、脑炎和由以下原因引起的失明 角膜感染)。了解HSV感染的不同途径 感染不同类型的人类细胞可以导致新类型的 阻止病毒进入细胞的抗病毒药物和设计 HSV活疫苗可能诱导免疫而不感染关键 神经系统之类的细胞。由该项目支持的研究 Grant导致了几种细胞表面蛋白的鉴定 与细胞表面糖胺多聚糖(GAG)共同作用的受体 介导HSV-1、HSV-2和两种动物甲型疱疹病毒的入侵 [伪狂犬病病毒(PRV)和牛疱疹病毒1型(BHV-1)]进入人 细胞。不同的人类细胞类型表达不同的辅酶-2亚群 受体，其中任何一个似乎都有足够的插嘴来 调停进入。协同受体的HSV配体被证明是GD 至少在两起案件中。下一阶段的具体目标和方法 包括：(1)使用工程杂交蛋白来鉴定 三种相关辅受体(HveB、HveC和PVR-)的结构域 HveD)负责其不同的进入活动频谱 上述病毒；(2)使用HSV突变体鉴定 每种蛋白共同介导病毒进入所需的HSV糖蛋白 受体，给出了初步迹象，病毒对 进入取决于细胞表达的蛋白质共受体；(3)使用 分子方法检测信使核糖核酸和蛋白质用于评估 人类单纯疱疹病毒进入辅受体在不同人群中的表达水平 细胞和组织以及用于进入的辅助受体的鉴定 在选定的培养的人类细胞类型中。所获得的结果应该是 确定HSV-1或HSV-2进入不同人群的决定因素 细胞类型以及病毒株和细胞敏感性的程度 以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.