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

项目总结 尽管经过长期的抗逆转录病毒治疗，人类的HIV感染和SIV/SIV感染恒河猴(RMS)仍在继续。 大量观察表明，CD8T细胞抑制HIV和SIV的复制。最近，两项研究 作为R01-AI-125064的一部分进行的研究表明：(I)CD8淋巴细胞是维持病毒所必需的 抗逆转录病毒治疗下的抑制(Cartwright，2016)；和(Ii)CD8耗尽揭示了一种强大的潜伏期逆转 白细胞介素15超级激动剂N-803的影响(麦克布莱恩，自然2020)。总体而言，这些研究揭示了 CD8淋巴细胞以前未知的功能，虽然其本质是抗病毒的，但在ART的背景下 可能矛盾的是，有利于拥有整合的、具有复制能力的CD4T细胞的长期存在 病毒。如果进一步得到证实，这一假说将对设计艾滋病毒“休克”产生深远的影响 基于调节CD8 T细胞潜伏期促进活性的治疗策略 促进重新激活病毒产生的CD4T细胞死亡的试剂。 这项建议的总体目标是更好地理解干预的最终潜力 去除CD8淋巴细胞以破坏SIV/SIV持续，减少甚至消除病毒库 在艺术之下。我们将以之前发布的数据为基础，使用高度相关、经过充分验证的模型 关于SIV/SIV感染猕猴(RM)的问题，回答了三个重要的问题：(I)什么是细胞 以及在ART治疗的SIV感染中观察到的强大和持久的病毒重新激活的解剖学来源 CD_8α去除和N-803R联合治疗后的RMS？(目标1)；(2)我们能清除CD4T细胞吗？ 在ART中CD8α或CD8β耗尽N-803后重新激活病毒生产- 用环境特异性广谱中和鸡尾酒治疗SHV感染的RMS 抗体(BNAbs)？(目标2)；以及(Iii)我们能否诱导重新激活病毒的CD4T细胞凋亡 在抗逆转录病毒治疗的SHV感染的RMS中应用CD8DNA耗尽N-803后的生产通过治疗 使用抗细胞凋亡分子Bcl2抑制剂的动物？(目标3)。 我们独一无二地准备进行拟议的实验工作，拥有一支经验丰富的 埃默里大学耶克斯国家灵长类研究中心的研究人员和关键资源。我们 因此相信我们将能够提供关于潜伏期如何促进活动的新的、关键的信息 可以在体内操纵CD8淋巴细胞的数量，以减少ART下的持久病毒库。

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.