Mechanism of HIV Cell-Cell Transmission of Relevance to Substance Users

与药物使用者相关的 HIV 细胞间传播机制

• 批准号: 8850415
• 负责人: HEINRICH GOTTLINGER
• 金额: $ 82.49万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850415
• 关键词: AIDS prevention; Binding; Blood Circulation; Cells; Data; Employee Strikes; Filopodia; Gagging; Goals; HIV; HIV-1; Health; Infection; Integrins; Lymphoid Cell; Membrane; Modeling; Molecular; Pathway interactions; Pharmaceutical Preparations; Play; Proteins; Recruitment Activity; Research; Role; T-Lymphocyte; Vaccination; Viral; Virion; Virus; Work; base; cohort; drug abuser; insight; intravenous injection; neutralizing antibody; novel; substance abuser; transmission process; virological synapse

DESCRIPTION: Cell-based transmission of HIV is far more efficient than the transfer of cell-free virus, and is likely to play a prominent role in HIV transmission when infected cells enter the bloodstream, as can occur during the intravenous injection of drugs by substance abusers. This may complicate vaccination efforts, because cell-based transmission allows HIV to evade neutralizing antibodies. An understanding of the molecular mechanisms underlying cell-to-cell transmission thus appears particularly relevant for the prevention of HIV transmission among drug abusers. We have identified the host proteins kindlin-3 and pacsin2 as novel binding partners HIV-1 Gag. Both proteins are dispensable for the completion of a full replication cycle after infection with cell-free virus. Nevertheless, both are essential for the spreading of HIV-1 among T cells, indicating that kindlin-3 and pacsin2 are critical for the cell-to-cell transmissionof HIV-1. Kindlin-3 is required for the function of integrins such as LFA-1, which has been implicated in HIV transmission. However, our data demonstrate a striking requirement for kindlin-3 for HIV-1 replication even in T lymphoid cells lacking LFA-1. Our working model is that HIV-1 Gag mimics the kindlin-recruiting activity of integrins to induce donor cell polarization towards the virological synapse and thereby promote virus transfer. Pacsin2 can generate membrane curvature and nucleate filopodia formation. HIV-1 frequently buds from filopodia, and viral filopodia capped by Gag have been implicated in HIV-1 cell-cell transmission. Thus, pacsin2 may be important for HIV-1 transmission because it is involved in viral filopodia formation. The goal of the project is to understand the roles of kindlin-3 and pacsin2, and of the cellular pathways in which these proteins are known to function, in the spreading of HIV-1. We also propose to investigate whether these pathways are altered among a cohort of elite controllers that includes drug abusers. The planned research may yield important translational insights into how to reduce HIV transmission among drug abusers.

描述：基于细胞的HIV的传播比无细胞病毒的转移更有效，并且当感染细胞进入血液时，可能在艾滋病毒传播中发挥着重要作用，就像静脉注射药物通过药物滥用者注射药物一样。这可能会使疫苗接种工作复杂化，因为基于细胞的传播允许HIV逃避中和抗体。因此，对细胞对细胞传播的分子机制的理解似乎与预防吸毒者中的HIV传播特别相关。 我们已经将宿主蛋白kindlin-3和pacsin2鉴定为新型结合伴侣HIV-1插科打蛋白。两种蛋白质都可以在用无细胞病毒感染后完成完整复制周期。然而，两者对于HIV-1在T细胞中的扩散至关重要，表明Kindlin-3和Pacsin2对于HIV-1的细胞到细胞传播至关重要。 Kindlin-3是整联蛋白（例如LFA-1）功能所必需的，LFA-1与HIV传播有关。但是，我们的数据表明，即使在缺乏LFA-1的T淋巴样细胞中，Kindlin-3的HIVLIN-3复制也有惊人的要求。我们的工作模型是，HIV-1 GAG模拟了整联蛋白的Kindlin征收活性，以诱导供体细胞极化对病毒学突触，从而促进病毒转移。 PACSIN2可以产生膜曲率和成核丝状形成。 HIV-1经常来自丝状的芽，而被GAG限制的病毒丝霉素与HIV-1细胞细胞传播有关。因此，PACSIN2对于HIV-1的传播可能很重要，因为它参与了病毒丝霉菌的形成。 该项目的目的是了解Kindlin-3和Pacsin2的角色，以及 这些蛋白质在HIV-1的扩散中已知这些蛋白质起作用。我们还建议研究这些途径是否在包括滥用药物在内的精英控制器中发生了变化。计划的研究可能会产生重要的转化见解，以了解如何减少滥用药物中的艾滋病毒传播。