Multiscale analysis of HIV-1 assembly, release, and cell-to-cell transmission

HIV-1 组装、释放和细胞间传播的多尺度分析

• 批准号: 9295126
• 负责人: Markus Thali
• 金额: $ 8.13万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-22 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295126
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adhesions; Biological Models; Cell Culture System; Cell fusion; Cell membrane; Cells; Collaborations; Face; Funding; Giant Cells; HIV; HIV-1; In Situ; In Vitro; Individual; Intervention; Intrinsic factor; Investigation; Longevity; Lymphoid Tissue; Maintenance; Mediating; Outcome; Pathogenesis; Proteins; Public Health; Research Personnel; Secure; Site; Structure; Surface; T-Lymphocyte; Testing; Viral; Virus; Virus Assembly; Virus Receptors; Work; base; env Glycoproteins; ezrin; humanized mouse; intravital imaging; killings; lymph nodes; migration; novel; particle; presynaptic; prevent; synaptogenesis; transmission process; viral transmission; virological synapse

HIV-1 disseminates rapidly in infected individuals. This can at least partially be attributed to virus transfer between T lymphocytes, which occurs very efficiently when infected and uninfected T cells directly contact each other, thus forming the so-called virological synapse (VS). While many features of this transient adhesion structure remain undefined, we know that VS formation necessitates an interaction of the viral envelope glycoprotein (Env), which is expressed at the surface of infected (virus producing) cells, with the viral receptor on uninfected (target) cells. It is not understood, however, why such interactions between Env, which mediates fusion of the viral particle with target cell membranes, and the viral receptor/coreceptor do not routinely result in producer-target cell fusion and thus the formation of a syncytium. Small T cell-based syncytia have been observed in lymph nodes of infected individuals and in humanized mice, but it is evident that most encounters between infected and uninfected cells resolve without fusion. Indeed, fusion-less encounters between these cells are a sine qua non for three central features of HIV-1 pathogenesis: cell-to-cell transmission, killing of bystander cells, and establishment and maintenance of a reservoir of latently infected T lymphocytes. Hence, revealing how fusion between infected and uninfected cells is regulated will not only contribute to our knowledge about how the virus can be efficiently transmitted from cell to cell, it will also aid understanding of key aspects of HIV-1 pathogenesis. We thus propose to investigate how both cell-intrinsic and cell-extrinsic factors, together, facilitate disengagement of producer and target cells upon virus transfer. It will also be tested whether enhancing fusion between the cells beyond the normal level is detrimental to virus dissemination.

HIV-1在感染者中传播迅速。这至少可以部分归因于病毒转移 当感染和未感染的T细胞直接接触时， 这就是所谓的病毒学突触（virological synapse，VS）。虽然这种瞬时粘附的许多特征 结构还不确定，我们知道VS形成需要病毒包膜的相互作用 糖蛋白（Env），其在感染的（产生病毒的）细胞表面表达，与病毒受体 未感染的（目标）细胞。然而，尚不清楚为什么介导蛋白质合成的Env之间存在这种相互作用。 通常不会导致病毒颗粒与靶细胞膜和病毒受体/辅助受体的融合 在生产者-靶细胞融合中，从而形成合胞体。基于小T细胞的合胞体已经被 在感染个体的淋巴结和人源化小鼠中观察到，但很明显， 感染细胞和未感染细胞之间的融合。事实上，这些之间的无融合接触 细胞是HIV-1发病机制的三个中心特征的必要条件：细胞间传播， 旁观者细胞，以及潜伏感染T淋巴细胞库的建立和维持。因此，我们认为， 揭示感染和未感染细胞之间的融合是如何调节的，不仅有助于我们的研究， 关于病毒如何有效地在细胞间传播的知识，也将有助于理解 HIV-1发病机制的关键方面。因此，我们建议研究细胞内在和细胞外在 这些因子共同促进了病毒转移时生产细胞和靶细胞的分离。它也将受到考验 增强细胞之间的融合超过正常水平是否不利于病毒传播。