HERPES SIMPLEX VIRUS ENTRY VIA ENDOCYTOSIS

单纯疱疹病毒通过内吞作用进入

• 批准号: 6808651
• 负责人: ANTHONY V NICOLA
• 金额: $ 15.52万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6808651
• 关键词: CHO cells; Herpes simplex disease; Vero cells; acid base balance; capsid; endocytosis; epithelium; herpes simplex virus 1; host organism interaction; human tissue; immunofluorescence technique; keratinocyte; latent virus infection; tissue /cell culture; virus envelope; virus infection mechanism; virus protein

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) remains a major human pathogen world-wide causing human diseases including cold sores, ocular and genital infections, neonatal infections and encephalitis. HSV establishes a life-long latent infection which reactivates periodically to produce recurrent disease. The long-term objective of this research is to define the mechanism of HSV entry into host cells. Understanding of the initial events in HSV infection may help develop new treatments and aid with viral targeting approaches for gene therapy protocols. HSV has long been recognized to enter some cells by pH-neutral fusion with the plasma membrane. Recently, we found that initial infection of some common cultured cell types requires endocytosis and low intracellular pH. Thus, HSV uses more than one pathway to deliver its genome to the cell interior. HSV infects many diverse cultured cell types and has multiple targets in vivo including cells of epithelial and neuronal origin. This relatively broad host range may be explained by multiple entry pathways. The process of HSV entry via endocytosis includes two sequential stages: internalization of intact, enveloped virus from the cell surface, and penetration of the capsid into the cytosol. I propose that these two stages are separable and have distinct molecular requirements. The specific aims of the proposed research are: (1) to characterize the cellular mechanism of HSV entry into human epithelial cells; and (2) to identify the viral requirements of HSV entry via endocytosis. A combination of molecular, biochemical and cell biological approaches will be used to achieve these goals. The results will define the determinants for entry of HSV into relevant human cell types. Additionally, these studies should elucidate the mechanisms that target the incoming virus to the proper cellular compartments to initiate productive infection.

描述（由申请人提供）：单纯疱疹病毒（HSV）仍然是世界范围内主要的人类病原体，引起人类疾病，包括唇疱疹、眼部和生殖器感染、新生儿感染和脑炎。 HSV 建立了终生潜伏感染，并定期重新激活以产生复发性疾病。这项研究的长期目标是明确 HSV 进入宿主细胞的机制。了解 HSV 感染的初始事件可能有助于开发新的治疗方法，并有助于基因治疗方案的病毒靶向方法。人们早已认识到 HSV 通过 pH 中性与质膜融合进入某些细胞。最近，我们发现一些常见培养细胞类型的初始感染需要内吞作用和低细胞内pH。因此，HSV 使用不止一种途径将其基因组递送至细胞内部。 HSV 感染许多不同的培养细胞类型，并具有多个体内靶标，包括上皮细胞和神经元来源的细胞。这种相对广泛的宿主范围可以通过多种进入途径来解释。 HSV 通过内吞作用进入的过程包括两个连续的阶段：完整的有包膜病毒从细胞表面的内化，以及衣壳渗透到细胞质中。我认为这两个阶段是可分离的并且具有不同的分子要求。本研究的具体目的是：（1）表征HSV进入人类上皮细胞的细胞机制； (2) 确定 HSV 通过内吞作用进入的病毒要求。将结合分子、生物化学和细胞生物学方法来实现这些目标。结果将确定 HSV 进入相关人类细胞类型的决定因素。此外，这些研究应阐明将传入病毒靶向适当的细胞区室以启动有效感染的机制。