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

CD8 T 细胞在 ART 治疗的 SIV 感染猕猴中的抗病毒作用

基本信息

批准号：
10593104
负责人：
Guido Silvestri
金额：
$ 91万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2026-03-31
项目状态：
未结题

项目摘要

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.

项目概要尽管进行了长期抗逆转录病毒治疗，人类的 HIV 感染和恒河猴 (RM) 的 SIV/SHIV 感染仍然持续存在。大量观察表明 CD8+ T 细胞抑制 HIV 和 SIV 复制。最近的两项研究。作为 R01-AI-125064 的一部分进行的研究表明： (i) CD8+ 淋巴细胞需要维持病毒 ART 下的抑制（Cartwright，Immunity 2016）；以及 (ii) CD8 耗竭揭示了强大的潜伏期逆转 IL-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 CD8+淋巴细胞以前未被认识到的功能，虽然其本质上具有抗病毒作用，但在ART环境中可能矛盾的是，有利于携带整合的、具有复制能力的 CD4+ T 细胞的长期存在如果进一步得到证实，这一假设将对设计艾滋病毒“休克”产生深远的影响。并杀死”基于调节 CD8+ T 细胞的潜伏期促进活性并结合促进重新激活病毒产生的 CD4+ T 细胞死亡的药物。该提案的总体目标是更好地了解基于以下因素的干预措施的最终潜力：去除 CD8+ 淋巴细胞以破坏 SIV/SHIV 持久性并减少甚至消除病毒库在 ART 下，我们将基于之前发布的数据并使用高度相关且经过充分验证的模型。恒河猴 (RM) 的 SIV/SHIV 感染的研究，回答三个重要问题：(i) 细胞有哪些在 ART 治疗的 SIV 感染者中观察到的强大且持久的病毒再激活的解剖学来源 CD8α 去除和 N-803 联合治疗后的 RM 可以清除 CD4+ T 细胞吗？在 CD8α 或 CD8β 耗尽 + ART 中施用 N-803 后重新激活病毒生产- 通过使用经过广泛中和处理的环境特异性鸡尾酒治疗动物来治疗 SHIV 感染的 RM 抗体 (bnAb)？（目标 #2）；以及 (iii) 我们能否诱导病毒重新激活的 CD4+ T 细胞凋亡？在 ART 治疗的 SHIV 感染 RM 中，CD8α 耗竭 + N-803 给药后的生产，通过治疗具有抗凋亡分子 Bcl-2 抑制剂的动物（目标#3）。我们拥有一支经验丰富的团队，准备好进行拟议的实验工作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。因此相信我们将能够提供关于延迟促进活动如何进行的新颖、关键的信息可以在体内操纵 CD8+ 淋巴细胞，以减少 ART 下的持久病毒库。