HIV Subversion of Innate Immunity

描述(由申请人提供)：在适应性免疫反应有机会形成之前，先天免疫反应向宿主发出感染警报。病毒核酸被引入细胞或在感染过程中合成，触发先天免疫的胞浆感受器产生抗病毒细胞因子，如I型干扰素(干扰素)。一些病毒可以逃避免疫感应。尽管HIV感染T细胞和巨噬细胞等靶细胞不能诱导固有的抗病毒干扰素反应，但感染急性期病毒血症的增加与DC的广泛激活和干扰素的激活有关。这项应用侧重于靶细胞的细胞内天然免疫，旨在了解艾滋病毒如何避免天然免疫激活。在首席调查员(PI)进行工作之前，细胞内 逆转录病毒特别是HIV的先天免疫识别一直是我们现有知识中关于病毒先天免疫识别的一个关键信息缺口。我们最近发现胞质外切酶TREX1抑制了HIV DNA引发的干扰素反应。在TREX1-/-小鼠细胞、人类CD4+T细胞和巨噬细胞中，TREX1被RNAi抑制，HIV DNA在胞浆中积累，HIV感染诱导干扰素的产生，从而抑制HIV的复制和传播。我们的研究表明，胞浆中的HIV DNA是一种关键的病原体相关分子模式(PAMP)，它可以通过天然免疫来检测，并激活干扰素和促炎细胞因子的产生，并且HIV利用宿主因子(如TREX1)来颠覆天然免疫检测。我们还提供了大量的初步数据，揭示了参与识别HIV DNA的胞浆DNA检测途径，以及TREX1抑制干扰素诱导的新机制。这项建议的具体目标是：1)确定先天免疫脱氧核糖核酸传感通路在识别胞浆艾滋病毒脱氧核糖核酸中的作用(S)。2)研究TREX1是如何抑制HIV天然免疫应答的。3)刻画HIV先天免疫检测和先天免疫逃避之间的对立动态如何有助于HIV感染的建立。我们的研究将阐明HIV如何颠覆天然免疫反应的分子机制，并为利用细胞内天然免疫作为一种新的治疗途径奠定基础。

DESCRIPTION (provided by applicant): The innate immune response alerts the host to infection before an adaptive immune response has a chance to develop. Viral nucleic acids introduced into cells or synthesized during infection trigger cytosolic sensors of innate immunity to produce antiviral cytokines, such as type I interferons (IFN). Some viruses evade immune sensing. The increase in viremia during acute stages of infection are associated with widespread activation of DCs and activation of IFN, although HIV infection of target cells such as T cells and macrophages does not induce intrinsic antiviral IFN responses. This application focuses on intracellular innate immunity in target cells and aims to understand how HIV avoids innate immune activation. Prior to work conducted by the Principal Investigator (PI), intracellular innate immune recognition of retroviruses especially HIV has been a key information gap in our existing knowledge regarding innate immune recognition of viruses. We recently discovered that the cytosolic exonuclease TREX1 suppressed the IFN response triggered by HIV DNA. In Trex1-/- mouse cells and human CD4+ T cells and macrophages in which TREX1 was inhibited by RNAi, HIV DNA accumulated in the cytosol and HIV infection induced IFN production that inhibited HIV replication and spreading. Our study suggested that cytosolic HIV DNA is a key pathogen-associated molecular pattern (PAMP) that can be detected by innate immunity and activate IFN and pro-inflammatory cytokine production, and that HIV exploits host factors (such as TREX1) to subvert innate immune detection. We also provide extensive preliminary data that uncover a cytosolic DNA detection pathway involved in the recognition of HIV DNA, and a novel mechanism by which TREX1 inhibits IFN induction. The specific aims of this proposal are 1) To define the role(s) of an innate immune DNA sensing pathway in the recognition of cytosolic HIV DNA. 2) To characterize how TREX1 inhibits the innate immune response to HIV. 3) To characterize how the opposing dynamic between HIV innate immune detection and HIV innate immune evasion contributes to the establishment of infection by HIV. Our proposed study will elucidate the molecular mechanisms of how HIV subvert innate immune responses, and lay the foundation for harnessing intracellular innate immunity as a novel avenue of therapeutics.