MOLECULAR REGULATION OF HIV-1 ASSEMBLY, RELEASE AND CELL-TO-CELL TRANSMISSION

HIV-1 组装、释放和细胞间传播的分子调控

• 批准号: 7959894
• 负责人: Markus Thali
• 金额: $ 4.08万
• 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: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959894
• 关键词: Adhesions; Affect; Cell fusion; Cell membrane; Cells; Computer Retrieval of Information on Scientific Projects Database; Consequences of HIV; Data; Development; Down-Regulation; Event; Funding; Genetic; Grant; HIV-1; In Vitro; Individual; Institution; Integral Membrane Protein; Kinetics; Knowledge; Laboratories; Lymphoid; Maintenance; Membrane; Membrane Fusion; Molecular; Organ; Pathogenesis; Process; Proteins; Regulation; Research; Research Personnel; Resources; Role; Source; Staging; Synapses; United States National Institutes of Health; Vermont; Viral; Virus; Virus Replication; base; human PHEMX protein; in vivo; insight; particle; transmission process; virological synapse

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Successful dissemination of HIV-1 in infected individuals depends on efficient transmission of viral particles from infected (producer) to uninfected (target) cells. In vitro propagation studies have established that HIV-1 particles are most effectively transmitted to target cells if they bud at the so-called virological synapse (VS) that forms between producer and target cells. Such synaptic virus transmission is most likely also prevalent in vivo, when HIV-1 spreads in secondary lymphoid organs of infected individuals. Hitherto, the events leading to the formation, maintenance and disassembly of the VS are poorly understood. Previously, we and other laboratories have established that HIV-1 particles exit from cells at membrane segments that are enriched in tetraspanins. These cellular integral membrane proteins are known to function as organizers of plasma membrane-based processes, including cell-cell fusion and adhesion, but their roles in virus replication, particularly during the late stages, remain to be elucidated. While some of our preliminary data suggest that the presence of tetraspanins at the virological presynapse may be beneficial for the virus, other available evidence suggests that these host cell proteins restrict virus spread. We thus hypothesize that HIV-1 evolved to spatially and temporally regulate tetraspanin expression levels such that it can disseminate efficiently. Altogether, these studies will provide further insight into the molecular mechanisms underlying HIV-1 spread and thus pathogenesis, and they may contribute knowledge that can be used for the development of anti-viral strategies. In the Specific Aims of this proposal we propose: 1) To analyze how tetraspanins inhibit HIV-1-induced membrane fusion, thus allowing cell-to-cell transfer without fusion of producer and target cell. 2) To investigate how, overall, tetraspanins in HIV-1 producer cells affect the transmission of viral particles to target cells. 3) To examine the kinetics, determinants and potential consequences of HIV-1-induced tetraspanin downregulation in infected cells.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 HIV-1在受感染个体中的成功传播取决于病毒颗粒从受感染（生产者）到未受感染（靶）细胞的有效传播。体外繁殖研究已经确定，如果HIV-1颗粒在生产细胞和靶细胞之间形成的所谓病毒学突触（VS）处出芽，则它们最有效地传播到靶细胞。当HIV-1在受感染个体的次级淋巴器官中传播时，这种突触病毒传播也很可能在体内流行。然而，导致VS形成、维持和解体的事件知之甚少。 以前，我们和其他实验室已经确定，HIV-1颗粒在富含四跨膜蛋白的膜段处离开细胞。已知这些细胞整合膜蛋白作为质膜为基础的过程，包括细胞-细胞融合和粘附的组织者，但它们在病毒复制中的作用，特别是在后期阶段，仍有待阐明。虽然我们的一些初步数据表明，四跨膜蛋白在病毒突触前的存在可能对病毒有益，但其他现有证据表明，这些宿主细胞蛋白限制了病毒的传播。因此，我们假设，HIV-1进化到空间和时间调节四跨膜蛋白的表达水平，使其能够有效地传播。总之，这些研究将进一步深入了解HIV-1传播的分子机制，从而发病机制，他们可能有助于知识，可用于开发抗病毒策略。 在本提案的具体目标中，我们提议： 1)分析四跨膜蛋白如何抑制HIV-1诱导的膜融合，从而允许细胞间转移而不使生产细胞和靶细胞融合。 2)研究HIV-1生产细胞中的四跨膜蛋白总体上如何影响病毒颗粒向靶细胞的传播。 3)研究HIV-1诱导的四跨膜蛋白在感染细胞中下调的动力学、决定因素和潜在后果。