ENTRY OF HERPES SIMPLEX VIRUS INTO CELLS

该项目的最终目标是确定单纯疱疹病毒(HSV)感染的机制。 入侵人类细胞以建立感染。这两种血清型中的一种或两种都会感染大多数人 在所有人口中都是人，是一系列疾病(复发性口腔和生殖器疾病)的原因 病变、新生儿严重播散性疾病、脑炎和角膜致盲 感染)。了解HSV感染不同类型的人类细胞的不同途径可以 导致了阻止病毒进入细胞的新型抗病毒药物和HSV活疫苗的设计 这可能会在不感染神经系统等关键细胞的情况下诱导免疫。研究 在这笔赠款的支持下，导致了几种细胞表面蛋白的鉴定，这些蛋白可以作为联合 细胞表面糖胺聚糖(GAG)受体介导HSV-1、HSV-2和HSV-2进入 动物甲型疱疹病毒[伪狂犬病病毒(PRV)和牛疱疹病毒1(BHV-1)]进入人类细胞。 不同的人类细胞类型表达不同的辅受体亚群，其中任何一个似乎都是 有足够的插嘴来调停进入。协同受体的HSV配体至少被证明是GD 两杯黑醋栗。下一阶段的具体目标和方法包括：(1)使用工程杂交蛋白质 用于鉴定三个相关的辅受体(HveB、HveC和Pvr-HveD)的结构域 对上述病毒不同的入侵活性负责；(2)使用单纯疱疹病毒突变体 为了鉴定由每个蛋白共受体介导的病毒进入所需的HSV糖蛋白， 有初步迹象表明，病毒的进入要求取决于所表达的蛋白质共受体 通过细胞检测；(3)用分子方法检测mRNA和蛋白质的表达情况 人单纯疱疹病毒共受体在不同细胞和组织中的水平及其鉴定 用于进入选定培养的人类细胞类型的受体。所获得的结果应该定义 HSV-1或HSV-2进入不同类型人类细胞的决定因素以及病毒株的程度 而细胞对进入的敏感性控制着感染在人类中的传播。

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 co- receptors 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 cassis. Specific aims and approaches for the next period include: (1) use of engineered hybrid proteins for ident fication of the structural domains of three related co-receptors (HveB, HveC andPvr-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 assessmentof the expression levels of human co-receptors for HSV entry in various human cells and tissues and identification of the co- receptors 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.