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.

产品说明：基于细胞的艾滋病毒传播比无细胞病毒的传播效率高得多，当受感染的细胞进入血液时，很可能在艾滋病毒传播中发挥重要作用，如药物滥用者静脉注射药物时可能发生的情况。这可能会使疫苗接种工作复杂化，因为基于细胞的传播使HIV逃避中和抗体。因此，了解细胞间传播的分子机制似乎对预防吸毒者之间的艾滋病毒传播特别重要。 我们已经确定了宿主蛋白kindlin-3和pacsin 2作为新的结合伴侣HIV-1 Gag。这两种蛋白质在无细胞病毒感染后都被激活以完成完整的复制周期。尽管如此，这两种蛋白都是HIV-1在T细胞中传播所必需的，这表明kindlin-3和pacsin 2对HIV-1的细胞间传播至关重要。 Kindlin-3是整合素如LFA-1的功能所必需的，LFA-1与HIV传播有关。然而，我们的数据表明，即使在缺乏LFA-1的T淋巴细胞中，HIV-1复制也需要kindlin-3。我们的工作模型是HIV-1 Gag模拟整合素的kindlin募集活性，以诱导供体细胞向病毒突触极化，从而促进病毒转移。 Pacsin 2可以产生膜弯曲和核丝状伪足的形成。HIV-1经常从丝状伪足出芽，并且被Gag覆盖的病毒丝状伪足与HIV-1细胞-细胞传播有关。因此，pacsin 2可能对HIV-1传播很重要，因为它参与病毒丝状伪足的形成。 该项目的目标是了解kindlin-3和pacsin 2的作用，以及 已知这些蛋白质在HIV-1传播中发挥作用的细胞途径。我们还建议调查这些途径是否在包括药物滥用者在内的精英控制者群体中发生改变。计划中的研究可能会对如何减少吸毒者中的艾滋病毒传播产生重要的转化见解。