Antiviral role of CD8+T cells in ART-treated SIV-infected macaques

项目摘要 尽管长期ART，人类的HIV感染和恒河猴（RM）的SIV/SHIV感染仍持续存在。 许多观察表明，CD 8 + T细胞抑制HIV和SIV复制。最近，两项研究 作为R 01-AI-125064的一部分进行的研究表明：（i）需要CD 8+淋巴细胞来维持病毒 ART下的抑制（Cartwright，Immunity 2016）;和（ii）CD 8耗竭揭示了强大的潜伏期逆转 白细胞介素-15超级激动剂N-803的作用（McBrien，Nature 2020）。总的来说，这些研究揭示了一个 以前未被认识到的CD 8+淋巴细胞的功能，虽然其性质是抗病毒的，但在ART的背景下 可能矛盾地有利于长期存在的CD 4 + T细胞窝藏整合，复制能力， 病毒如果得到进一步证实，这一假设将对设计艾滋病毒“休克”产生深远影响 基于调节CD 8 + T细胞的潜伏期促进活性的“杀死”治疗策略与 促进重新激活病毒产生的CD 4 + T细胞死亡的药物。 本提案的总体目标是更好地了解基于以下方面的干预措施的最终潜力： 去除CD 8+淋巴细胞以破坏SIV/SHIV的持续存在并减少甚至消除病毒库 我们将建立在我们以前公布的数据，并使用高度相关的，经过验证的模型 SIV/SHIV感染的恒河猴（RM），回答三个重要的问题：（i）什么是细胞 在ART治疗的SIV感染者中观察到的强大和持久的病毒再活化的解剖学来源 联合CD 8 α耗竭和N-803？(Aim#1）;（ii）我们能否清除CD 4 + T细胞 在ART中，CD 8 α或CD 8 β耗竭+ N-803给药后重新激活病毒产生， 通过用Env特异性广泛中和的混合物治疗动物来治疗SHIV感染的RM， 抗体（bnAbs）？(Aim#2）;和（iii）我们能否诱导具有再活化病毒的CD 4 + T细胞的凋亡 ART治疗的SHIV感染RM中CD 8 α耗竭+ N-803给药后， 动物与抑制剂的抗凋亡分子Bcl-2？(Aim#3）。 我们是唯一准备进行拟议的实验工作，与一个有成就的团队， 埃默里大学耶基斯国家灵长类动物研究中心的研究人员和关键资源。我们 因此，我们相信，我们将能够提供新的，关键的信息，如何潜伏期促进活动， 的CD 8+淋巴细胞可以在体内操作，以减少ART下的持久性病毒库。

PROJECT SUMMARY HIV infection of humans and SIV/SHIV infection of rhesus macaques (RMs) persist despite long-term ART. Numerous observations indicate that CD8+ T cells inhibit HIV and SIV replication. More recently, two studies conducted as part of R01-AI-125064 have shown that: (i) CD8+ lymphocytes are required to maintain virus suppression under ART (Cartwright, Immunity 2016); and (ii) CD8 depletion reveals a powerful latency-reversal effect by the interleukin-15 super-agonist N-803 (McBrien, Nature 2020). Collectively, these studies revealed a previously unrecognized function of CD8+ lymphocytes that, while antiviral in its nature, in the setting of ART may paradoxically favor the long-term persistence of CD4+ T cells harboring integrated, replication-competent virus. If further confirmed, this hypothesis would have profound implications in terms of designing HIV “shock and kill” cure strategies based on modulating the latency promoting activity of CD8+ T cells in combination with agents that would promote the demise of the CD4+ T cells that have reactivated virus production. The overarching aim of this proposal is to better understand the ultimate potential of interventions based on the removal of CD8+ lymphocytes to disrupt SIV/SHIV persistence and reduce or even eliminate the virus reservoir under ART. We will build upon our previously published data and use the highly relevant, well validated model of SIV/SHIV infection of rhesus macaques (RM), to answer three important questions: (i) what are the cellular and anatomic sources of the robust and persistent virus reactivation observed in ART-treated SIV-infected RMs after combined treatment with CD8α depletion and N-803? (Aim #1); (ii) can we clear the CD4+ T cells that have reactivated virus production following CD8α or CD8β depletion + N-803 administration in ART- treated SHIV-infected RMs by treating the animals with a cocktail of Env-specific broadly neutralizing antibodies (bnAbs)? (Aim #2); and (iii) can we induce apoptosis of the CD4+ T cells that have reactivated virus production following CD8α depletion + N-803 administration in ART-treated SHIV-infected RMs by treating the animals with an inhibitor of the anti-apoptotic molecule Bcl-2? (Aim #3). We are uniquely poised to conduct the proposed experimental work, with an accomplished team of investigators and key resources at the Yerkes National Primate Research Center of Emory University. We therefore believe that we will be able to provide novel, critical information on how the latency promoting activity of CD8+ lymphocytes can be manipulated in vivo to reduce the persistent virus reservoir under ART.