Mechanisms of CTL Resistance in HIV Reservoirs

项目总结/摘要 虽然现代疗法大大改善了艾滋病毒感染者的前景，但他们无法 治疗感染，使这些人终身承担抗逆转录病毒（ARV）药物的负担。 对于任何特定的个人，保持终身坚持服药可能会带来巨大的挑战。 此外，许多人无法获得这些昂贵的药物，特别是那些生活在 资源有限的环境。因此，开发新的疗法将具有巨大的价值， 治愈艾滋病毒感染或使其缓解（一种病毒水平保持较低或检测不到的状态，即使 停止服用抗逆转录病毒药物）。实现治愈或缓解的一种方法是重新激活潜伏的 （隐藏的）病毒“储库”，并利用免疫系统来减少或消除这些储库。这是踢 “杀死”方法通常集中在细胞毒性T细胞（CTL）上，这是免疫系统的一个分支，专门用于 清除病毒感染的细胞。虽然“踢杀”策略在体外潜伏期模型中显示出了希望，但它 尚未在临床试验中有效。在最近的工作中，我们发现了消除 通过显示HIV感染细胞对CTL具有内在抗性-即使它们被强迫 通过潜伏期逆转剂（LRA）将病毒展示给免疫系统。虽然这种内在阻力的观点 在HIV背景下，CTL尚未被广泛考虑，但众所周知，它是限制治疗的一个因素， 在癌症中的功效。在这项资助申请中，我们建议利用尖端技术来识别新的 靶细胞抵抗CTL消除的机制。预计这些方法将产生大量 “命中”的数量，我们将对其进行高分辨率的机械表征。然后我们将研究 从艾滋病毒感染者中提取样本，以确定这些耐药机制中哪些在艾滋病毒中发挥作用 体内持久性。最后，我们将直接测试针对这种抗性的疗法是否可以让CTL杀死 这些离体的携带抗逆转录病毒药物的细胞。我们希望我们的研究结果将是确定新的 开发旨在治愈艾滋病毒感染或缓解的疗法的目标。更广泛地说，我们 预计这里确定的机制将为CTL生物学提供基本的见解， 对癌症和其他疾病的影响。

PROJECT SUMMARY/ABSTRACT Although modern therapies have dramatically improved the outlooks for people living with HIV, they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication. For any given individual, maintaining lifelong adherence to medication can present substantial challenges. Moreover, many people do not have access to these expensive medications - in particular those living in resource-limited settings. It would therefore be of tremendous value to develop novel therapies that can either cure HIV infection or drive it into remission (a state where levels of virus remain low or undetectable even when one stops taking ARV medication). One approach to achieving either a cure or remission is to reactivate latent (hidden) ‘reservoirs’ of virus and harness the immune system to reduce or eliminate these reservoirs. These ‘kick & kill’ approaches often focus on cytotoxic T-cells (CTL), which are an arm of the immune system specialized in eliminating virus-infected cells. While the ‘kick & kill’ strategy has shown promise in in vitro models of latency, it has not yet been effective in clinical trials. In recent work, we have uncovered an additional barrier to eliminating viral reservoirs by showing that HIV-infected cells are intrinsically resistant to CTL - even when they are forced to show virus to the immune system by latency reversing agents (LRAs). Although this idea of intrinsic resistance to CTL has not been widely considered in the context of HIV, it is well known as a factor that limits therapeutic efficacy in cancer. In this grant application we propose to leverage cutting edge technologies to identify novel mechanisms by which target cells resist elimination by CTL. These approaches are expected to yield a large number of ‘hits’, for which we will perform high-resolution mechanistic characterizations. We will then study samples from people living with HIV to determine which of these mechanisms of resistance play roles in HIV persistence in vivo. Finally, we will directly test whether therapies targeting this resistance can allow CTL to kill these ex vivo reservoir-harboring cells. We expect that the outcome of our study will be the identification of novel targets for the development of therapies aimed at curing HIV infection or enabling remission. More broadly, we anticipate that the mechanisms identified here will provide fundamental insights into the biology of CTL with implications for cancer & other conditions.