Studies of Herpes Simplex Virus Glycoproteins

单纯疱疹病毒(HSV)会导致人类疾病，包括唇疱疹、眼睛和生殖器感染、新生儿感染和脑炎。HSV1和HSV2在感觉神经节内建立终生潜伏感染，反复感染是常见的。美国和世界各地的许多人都感染了HSV的一种或两种血清型，越来越多的证据表明，HSV2感染有助于艾滋病毒的传播。单纯疱疹病毒仍然是世界范围内人类的主要病原体，导致唇疱疹、眼睛和生殖器感染、失明、脑炎和新生儿感染。感染后，糖蛋白在细胞膜上表达，是宿主免疫反应的主要目标。病毒包膜含有11种糖蛋白，它们对感染和致病都很重要。我们的长期目标是了解HSV糖蛋白相互作用以及与细胞分子相互作用以介导HSV进入哺乳动物细胞的机制。Gd、Gb和Gh/Gl复合体是病毒侵入所必需的四种糖蛋白。糖蛋白D是单纯疱疹病毒包膜的一个结构成分，是病毒与细胞上的受体稳定结合以及病毒包膜与质膜融合所必需的。病毒的入侵首先是由GD与其受体之一之间的相互作用触发的。这种相互作用然后触发下游事件，这些事件必然涉及由Gb和Gh/Gl组成的核心融合机制。一个重要的问题是：Gd与其(S)受体之间的相互作用如何触发Gb和Gh/gl的作用而导致融合？我们回答这个复杂问题的方法是研究病毒粒子糖蛋白和受体的结构和功能。因此，我们提出了三个具体的目标：1)进一步研究gD结构及其与病毒进入的关系；2)探索gD与其细胞受体结合后病毒进入的步骤；3)对HSV1和HSV-2的Gh/g1进行结构-功能研究。我们的研究将为HSV进入的具体步骤提供信息，对疱疹病毒领域以及更大的病毒进入领域具有重要意义。在更实际的层面上，我们的发现将被应用于针对HSV1和HSV2的疫苗和新疗法的开发。

Herpes simplex viruses (HSVs) cause human diseases, including cold sores, eye and genital infections, neonatal infections and encephalitis. HSVl and HSV2 establish lifelong latent infections within sensory ganglia and recurrent infections are common. Many people in the U.S. and worldwide are infected by one or both serotypes of HSV and there is increasing evidence that HSV2 infections contribute to the spread of HIV. HSV remains a major human pathogen worldwide, causing cold sores, eye and genital infections, blindness, encephalitis, and neonatal infections. After infection, glycoproteins are expressed on the cellular membranes and are major targets ofthe host's immune response. The virus envelope contains eleven glycoproteins that are important for infection and pathogenesis. Our long term objective is to understand the mechanisms by which HSV glycoproteins interact with each other and with cell molecules to mediate HSV entry into mammalian cells. Four glycoproteins, gD, gB and a complex of gH/gL are essential for virus entry. Glycoprotein D, a structural component ofthe HSV envelope is necessary for the stable binding of the virus with receptors on cells as well as fusion ofthe virus envelope with the plasma membrane. Virus entry is triggered first by the interaction between gD and one of its receptors. This interaction then triggers downstream events that necessarily involve the core fusion machinery consisting of gB and gH/gL. An important question is: how does the interaction between gD and it(s) receptor trigger action by gB and gH/gL to cause fusion? Our approach to answering this complex question has been to study the structure and function of both the virion glycoproteins and receptors. Therefore, we propose three specific aims: 1) To further characterize gD structure and its relationship to virus entry; 2) To explore the steps of virus entry that occur after gD binds its cell receptor; and 3) To carry out structure-function studies of gH/gL of HSVl and HSV- 2. Our studies should provide information about the specific steps of HSV entry and have significance for the herpesvirus field as well as for the larger field of virus entry. On a more practical level, our findings should find application for development of vaccines and new therapeutics against HSVl and HSV2.