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

描述：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突出作用，就像吸毒者静脉注射药物时发生的那样。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艾滋病毒逃避中和抗体。因此，了解细胞间传播的分子机制似乎对预防吸毒者中的艾滋病毒传播特别重要。我们已经鉴定了宿主蛋白kindlin-3和pacsin2是新的结合伙伴HIV-1 Gag。在感染无细胞病毒后，这两种蛋白质对于完成完整的复制周期是必不可少的。然而，两者对于HIV-1在T细胞中的传播都是必不可少的，这表明Kindlin-3和Pacsin2对于HIV-1的细胞间传播至关重要。Kindlin-3是LFA-1等整合素发挥功能所必需的，LFA-1与HIV传播有关。然而，我们的数据显示，即使在缺乏LFA-1的T淋巴细胞中，也需要Kindlin-3来复制HIV-1。我们的工作模型是，HIV-1 Gag模拟整合素的点燃招募活性，诱导供体细胞极化到病毒学突触，从而促进病毒转移。Pacsin2能产生膜曲率和有核的丝状足孔的形成。HIV-1经常从丝状伪足和由GAG覆盖的病毒丝状伪足中萌发，这与HIV-1的细胞间传播有关。因此，Pacsin2可能对HIV-1的传播很重要，因为它参与了病毒丝状足的形成。该项目的目标是了解kindlin-3和pacsin2的作用，以及 已知这些蛋白质在HIV-1传播中起作用的细胞途径。我们还建议调查这些通路是否在包括吸毒者在内的精英控制者队列中发生了改变。这项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翻译见解。

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.