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Role of cell polarity regulators in HIV spreading

细胞极性调节剂在 HIV 传播中的作用

基本信息

批准号：
10323026
负责人：
HEINRICH GOTTLINGER
金额：
$ 53.28万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323026
关键词：
Actins Antigen-Presenting Cells CD4 Positive T Lymphocytes CDC42 gene Cell Line Cell Polarity Cells Complex Cues Cytoskeleton Data Drug Targeting Eukaryotic Cell Exocytosis FMNL1 gene Family Filopodia Golgi Apparatus Guanosine Triphosphate Phosphohydrolases HIV HIV-1 Human Infection Investigation Knock-out Life Cycle Stages Mediating Membrane Microtubule-Organizing Center Microtubules Modeling Molecular Monomeric GTP-Binding Proteins PAK-1 kinase PARD6A gene Peripheral Blood Mononuclear Cell Phosphotransferases Polymerase Process Protein Kinase Proteins Public Health Reporting Role Secretory Vesicles Signal Pathway Site Surface T-Lymphocyte Vesicle Viral Virion Virus Yeasts cdc42 GTP-Binding Protein cytokine experimental study immunological synapse formation insight man polarized cell polymerization reconstitution response synaptogenesis trafficking transmission process virological synapse

项目摘要

ABSTRACT HIV-1-infected T cells can form stable conjugates with non-infected T cells in a process known as “virological synapse” formation. This process is reminiscent of the formation of an “immunological synapse”, during which CD4+ T cells rapidly polarize the actin cytoskeleton, the microtubule-organizing center (MTOC), and cytokine- containing vesicles towards antigen-presenting cells. The polarization of CD4+ T cells during immunological synapse formation depends on the RHO family GTPase CDC42, a molecular switch that has a key role in the establishment of polarity in eukaryotic cells. We have now observed that CDC42 is critical for the efficient spreading of HIV-1 in several T cell lines and in primary cells. However, our data also imply that CDC42 is dispensable for the completion of a single cycle of replication. Together, our observations implicate CDC42 in the cell-to-cell transmission of HIV-1. CDC42 stimulates the formation of membrane extensions, such as filopodia, through effectors that mediate the polarization of the actin cytoskeleton, and HIV-1 can exploit filopodial bridges to spread from cell to cell. Thus, our data let us to propose a working model in which CDC42 is crucial for the formation of intercellular extensions that facilitate the transfer of HIV-1 between CD4+ T cells. In support of this model, we have observed that CDC42 is required for the formation of HIV-1-induced membrane extensions by MOLT-3 cells. An alternative working model is that CDC42 is required for the polarized trafficking of HIV-1 virion components to the virologic synapse. We propose to directly examine the roles of CDC42 in HIV-1 cell-to-cell transmission and virological synapse formation, and to determine whether HIV-1 regulates the activity of CDC42. We also propose to examine the roles of CDC42 effectors that regulate localized actin assembly and polarized trafficking in HIV-1 spreading. Among these effectors are F-BAR proteins that connect to actin polymerization machinery, as does the F-BAR protein PACSIN2, which we have recently implicated in the cell-to-cell transmission of HIV-1. Notably, our preliminary results indicate that certain CDC42 effectors, including the CDC42-regulated actin polymerase FMNL1 and a putative CDC42 effector that controls polarized exocytosis, have crucial roles in HIV-1 replication. The proposed studies have the potential to yield fundamental new insights into the mechanism of an important but poorly understood mode of HIV-1 transmission. Of particular significance would be the identification of a kinase downstream of CDC42 as being critical for HIV-1 spreading, since protein kinases constitute one of the most important groups of drug targets.

摘要