HIV Subversion of Innate Immunity

描述（由申请人提供）：先天性免疫反应在适应性免疫反应有机会发展之前提醒宿主感染。引入细胞或在感染期间合成的病毒核酸触发先天免疫的胞质传感器以产生抗病毒细胞因子，例如I型干扰素（IFN）。一些病毒逃避免疫感应。在感染的急性阶段期间病毒血症的增加与DC的广泛活化和IFN的活化相关，尽管靶细胞如T细胞和巨噬细胞的HIV感染不诱导内在的抗病毒IFN应答。该应用程序侧重于靶细胞的细胞内先天免疫，旨在了解HIV如何避免先天免疫激活。在主要研究者（PI）开展工作之前， 逆转录病毒特别是HIV的先天免疫识别是我们现有的关于病毒先天免疫识别的知识中的关键信息缺口。我们最近发现胞质核酸外切酶TREX 1抑制HIV DNA引发的IFN反应。在Trex 1-/-小鼠细胞和人CD 4 + T细胞和巨噬细胞中，其中TREX 1被RNAi抑制，HIV DNA在细胞质中积累，HIV感染诱导IFN产生，抑制HIV复制和传播。我们的研究表明，胞质HIV DNA是一种关键的病原体相关分子模式（PAMP），可以通过先天免疫检测并激活IFN和促炎细胞因子的产生，HIV利用宿主因子（如TREX 1）来破坏先天免疫检测。我们还提供了大量的初步数据，揭示了参与识别HIV DNA的胞质DNA检测途径，以及TREX 1抑制IFN诱导的新机制。该提议的具体目的是1）确定先天免疫DNA传感途径在识别胞质HIV DNA中的作用。2)描述TREX 1如何抑制对HIV的先天免疫反应。3)为了表征HIV先天免疫检测和HIV先天免疫逃避之间的对立动态如何有助于HIV感染的建立。我们提出的研究将阐明HIV如何破坏先天免疫反应的分子机制，并为利用细胞内先天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.