Enhancing Susceptibility of HIV Reservoirs to CTL Through a Discovery to Translational Approach

项目总结/摘要 虽然现代抗逆转录病毒疗法（ARV）已经大大改善了患有艾滋病的人的前景， 艾滋病毒，他们无法治愈感染。对于艾滋病毒感染者来说，治愈意味着摆脱许多负担， 包括耻辱、昂贵的药物和炎症相关的合并症。治疗方法也会 公共卫生福利，是帮助结束艾滋病毒流行的有力工具。开发治疗艾滋病毒的方法 需要了解病毒是如何在人体内持续数年甚至数十年的，即使是新的病毒， 一轮轮的细胞感染（复制）被抗逆转录病毒药物阻断，尽管抗病毒药物持续存在， 免疫反应。主要的模式是病毒以潜伏状态隐藏在受感染的细胞中， 因此免疫反应是看不见的。因此，治愈感染的努力集中在治疗上， 逆转HIV潜伏期以使这些细胞暴露于消除，但迄今为止产生了令人失望的结果。这个， 沿着几条证据的汇合线，已经导致了更近的假设， 系统可能不是艾滋病毒持续存在的唯一机制-而是这些罕见的感染人群 可以选择对细胞毒性T淋巴细胞杀伤具有细胞内在抗性的细胞， 即使当它们表达抗原并被看到时。这与免疫肿瘤学的最新发现相似， 现在已经很好地确定，一些免疫原性肿瘤经历了细胞内在抗性的选择， CTL.对于这个项目，我们组建了一个团队，其中包括建立CTL机制的先驱 和两位HIV专家，他们提出了在这种情况下CTL抗性的想法， 一系列体外研究。通过合并这些专业领域，我们的目标是全面描述 HIV感染的原代CD 4 + T细胞中CTL抗性的机制，并辨别其中哪些在HIV感染中起作用。 来自艾滋病病毒携带者的真实的艾滋病病毒储存细胞。我们将根据这些结果选择治疗靶点， 确定将这些与HIV特异性CTL和潜伏期逆转策略整合的组合方法， 实现离体特异性消除携带HIV病毒的细胞。我们还将利用创新鼠标 该模型用于测试是否接合这些治疗靶点限制了体内HIV储库的播种。结果 因此，该项目的主要目的是：i）为理解HIV中的CTL抗性奠定广泛的基础， 和ii）多个治疗靶点的临床前验证，其有可能有助于治愈 艾滋病。

PROJECT SUMMARY/ABSTRACT Although modern antiretroviral (ARV) therapies have dramatically improved the outlooks for people living with HIV, they are unable to cure infection. For people with HIV a cure would represent freedom from many burdens, including stigma, expensive medications, and inflammation-associated co-morbidities. A cure would also have public health benefits, comprising a powerful tool to help end the HIV epidemic. Developing a cure for HIV requires developing an understanding of how the virus persists for years and decades in people, even when new rounds of cellular infection (replication) are blocked by ARVs, and despite the ongoing presence of antiviral immune responses. The dominant paradigm has been that the virus hides in a latent state in infected cells and is thus invisible to immune responses. Efforts to cure infection have therefore focused on therapeutically reversing HIV latency to expose these cells to elimination but have thus far yielded disappointing results. This, along with several converging lines of evidence, have led to more recent hypothesis that hiding from the immune system may not be the only mechanism by which HIV persists – but rather that these rare populations of infected cells may have been selected for those that possess cell-intrinsic resistance to killing by cytotoxic T-lymphocytes, even when they express antigen and are seen. This parallels recent findings from ImmunoOncology where it has now been well established that some immunogenic tumors undergo selection for cell-intrinsic resistance to CTL. For this project, we have assembled a team comprising a pioneer in establishing mechanisms of CTL resistance in tumors, and two HIV experts who have advanced the idea of CTL resistance in this setting through a series of ex vivo studies. By merging these areas of expertise, we Aim to comprehensively describe mechanisms of CTL resistance in HIV-infected primary CD4+ T-cells and to discern which of these are at play in real HIV reservoir cells from people with HIV. We will build from these results to select therapeutic targets and identify combination approaches that integrate these with HIV-specific CTL and latency reversal strategies to achieve specific elimination of HIV reservoir-harboring cells ex vivo. We will also leverage an innovative mouse model to test whether engaging these therapeutic targets limits the seeding of HIV reservoirs in vivo. The results of this project are thus expected to be: i) laying a broad foundation for understanding CTL resistance in the HIV reservoir and ii) pre-clinical validation of multiple therapeutic targets with the potential to contribute to a cure for HIV.