TIM-mediated Inhibition of HIV Release: Cooperation with SERINC and Antagonism by Nef

大多数抗病毒限制因素是干扰素(干扰素)诱导的，因此统称为 作为干扰素刺激基因(ISGs)；然而，许多不受干扰素直接调节，仍然很差 特色化的。值得注意的是，这些细胞因子中的一些已知可以调节脂质和/或膜特性， 从而扰乱艾滋病毒和其他病毒的复制。这一类别最近的两个例子是Tim(T- 细胞免疫球蛋白和粘蛋白结构域)和丝氨酸结合蛋白(SerinC)家族蛋白，它们直接相互作用 通过或可能调节磷脂酰丝氨酸(PS)的合成，从而抑制艾滋病毒的释放或传染性。 有趣的是，我们的初步数据和最近发表在《自然》杂志上的两篇报告显示，慢病毒Nef 蛋白质能有效地拮抗TIMs和SERINCs的限制。此外，我们最近观察到， SERINC蛋白增强TIM-1阻断HIV-1释放的能力，SERINC通过稳定SERINC来实现这一作用 TIM在病毒产生细胞中的表达。在这个应用中，我们建议测试几个新的假设 这解决了TIM、SERINC、PS和Nef之间可能存在的联系。AIM 1将决定HIV-1 Nef如何 通过调节TIM-1的合成和转运来拮抗TIM介导的病毒释放抑制 和PS。目标2将重点了解内源性SERINC蛋白在CD4+T细胞中的作用 调节TIM的表达和稳定性，以及调节病毒产生细胞和病毒中的脂质 这些微粒共同有助于抑制艾滋病毒-1的释放和复制。目标3将定义分子 SERINC和TIM蛋白在病毒产生细胞中的相互作用，并剖析HIV-1Nef蛋白如何下调- 调节这一过程以促进HIV-1的产生和感染。拟议中的实验结果将 对TIM、SERINC和HIV Nef之间的相互作用提供新颖和统一的机制见解，并将 提高我们对病毒-宿主相互作用和艾滋病发病机制的认识。

The majority of antiviral restriction factors are interferon (IFN) inducible, and are thus collectively referred to as IFN-stimulated genes (ISGs); many, however, are NOT directly regulated by IFN and remain poorly characterized. Notably, some of these cellular factors are known to modulate lipids and/or membrane properties, thereby disrupting the replication of HIV and other viruses. Two recent examples from this category are TIM (T- cell immunoglobulin and mucin domain) and SERINC (serine incorporator) family proteins, which directly interact with or possibly regulate the synthesis of phosphatidylserine (PS), thus inhibiting HIV release or infectivity. Interestingly, our preliminary data and two recent reports published in Nature showed that the lentiviral Nef proteins effectively antagonize the restriction by TIMs and SERINCs. Moreover, we have recently observed that SERINC proteins potentiate the ability of TIM-1 to block HIV-1 release and that SERINCs do this by stabilizing the TIM expression in the viral producer cells. In this application, we propose to test several novel hypotheses that address the possible link between TIM, SERINC, PS and Nef. Aim 1 will determine how HIV-1 Nef antagonizes TIM-mediated inhibition of viral release through modulating the synthesis and trafficking of TIM-1 and PS. Aim 2 will focus on understanding of the role of endogenous SERINC proteins in CD4+ T cells that regulates the TIM expression and stability, as well as in modulating lipids in the viral producer cell and viral particles, collectively contributing to the inhibition of HIV-1 release and replication. Aim 3 will define the molecular interplay between SERINC and TIM proteins in viral producer cells, and dissect how HIV-1 Nef protein down- modulates this process to promote HIV-1 production and infection. Results from the proposed experiments will provide novel and unified mechanistic insights into the interplay between TIM, SERINC and HIV Nef, and will enhance our understanding of virus-host interaction and AIDS pathogenesis.