Structural and mechanistic studies of herpesvirus entry into host cells

疱疹病毒是人类的病原体，会终身感染宿主，导致唇疱疹， 生殖器疱疹、失明、脑炎、癌症和危及生命的疾病 免疫受损的个体。我的研究目标是了解原子学- 详细说明疱疹病毒是如何进入宿主细胞的。这些信息将是无价的 设计抗疱疹病毒疗法以同时对抗病毒感染和细胞-细胞 散开。 疱疹病毒进入细胞的机制非常复杂。而另一个则被封住 病毒使用一种蛋白质来影响细胞进入，所有疱疹病毒都需要至少三种蛋白质 蛋白质：Gb、Gh和Gl。这三种蛋白质被认为完成了 病毒和细胞膜-病毒进入的关键一步-但它们的确切功能是 默默无闻。我的目标是确定单纯疱疹病毒gB和Gh/gl蛋白如何 (HSV)共同完成膜融合以及来自 受体结合蛋白，Gd，触发膜融合机制。揭开如何 这些在HSV感染中起作用的蛋白质也将揭示它们在其他 疱疹病毒，因为膜融合机制，即Gb，Gh和Gl是高度 保守的。我的方法将结合x射线结晶学的力量来确定 单个蛋白质的结构具有其他生物物理和生物化学的严格性 研究它们相互作用的技术。这项研究的结果将是一个彻底的 疱疹病毒介导的病毒融合的确定和精细详细的图像 和细胞膜。 以前在单组分系统中病毒介导的膜融合的研究已经 为膜融合的一般机制提供了许多重要的见解， 参与了许多正常的细胞过程。但复杂的多蛋白融合 疱疹病毒机制是调节的、多组分的细胞的更好的模型 膜融合。因此，如果我们确定疱疹病毒糖蛋白是如何与 在细胞进入过程中驱动膜融合，我们将从根本上提升我们的机制 对膜融合的理解。

Herpesviruses are human pathogens that infect their hosts for life, causing cold sores, genital herpes, blindness, encephalitis, cancers, and life-threatening conditions in immuno-compromised individuals. The goal of my research is to understand in atomic- level detail how herpesviruses enter host cells. Such information will be invaluable in designing anti-herpesvirus therapeutics to combat both viral infections and cell-cell spread. The herpesvirus cell-entry mechanism is very complex. Whereas other enveloped viruses use a single protein to effect cell entry, all herpesviruses require at least three proteins: gB, gH, and gL. These three proteins are thought to accomplish the fusion of viral and cell membranes – a pivotal step in viral entry – but their exact functions are obscure. I aim to determine how the gB and gH/gL proteins of Herpes Simplex Virus (HSV) work together to accomplish membrane fusion and how the signal from the receptor-binding protein, gD, triggers the membrane-fusion machinery. Uncovering how these proteins work in HSV infection will also reveal their functions in other herpesviruses because the membrane-fusion machinery, i.e., gB, gH, and gL, is highly conserved. My approach will combine the power of x-ray crystallography to determine the structures of individual proteins with the rigor of other biophysical and biochemical techniques to study their interactions. The outcome of this research will be a thoroughly determined and finely detailed picture of the herpesvirus-mediated fusion of the viral and cell membranes. Previous studies of virus-mediated membrane fusion in single-component systems have provided many crucial insights into the general mechanism of membrane fusion, involved in many normal cellular processes. But the complex multiprotein fusion machinery of herpesviruses is a better model for the regulated, multi-component cellular membrane fusion. Therefore, if we establish how herpesvirus glycoproteins interact to drive membrane fusion during cell entry, we will advance fundamentally our mechanistic understanding of membrane fusion.