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

• 批准号: 10258652
• 负责人: Guido Silvestri
• 金额: $ 91万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10258652
• 关键词: Agonist; Anatomy; Animal Model; Animals; Antiviral Agents; Apoptosis; Apoptotic; Autopsy; BCL2 gene; Bar Codes; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Combined Modality Therapy; Data; Excision; Genetic Transcription; HIV; HIV Infections; Human; Immunity; In Vitro; Individual; Infection; Interleukin-15; Interruption; Intervention; Location; Lymphocyte Depletion; Macaca; Macaca mulatta; Maintenance; Measures; Mediating; Modeling; Natural Killer Cells; Nature; Primates; Production; Publishing; Research; Research Personnel; Resources; Role; SIV; Science; Shock; Source; Suicide; T-Lymphocyte Subsets; Testing; Tissues; Universities; Viral reservoir; Virus; Virus Latency; Virus Replication; Work; antiretroviral therapy; base; design; in vivo; inhibitor/antagonist; mimetics; neutralizing antibody; novel; simian human immunodeficiency virus

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.

项目摘要 人类的艾滋病毒感染和恒河猕猴（RMS）的SIV/SHIV感染持久目的地长期艺术。 许多观察结果表明，CD8+ T细胞抑制HIV和SIV复制。最近，两项研究 作为R01-AI-125064的一部分进行的表明：（i）CD8+淋巴细胞需要维持病毒 在艺术下的抑制（Cartwright，Immunity 2016）； （ii）CD8耗竭揭示了强大的延迟反转 Interleukin-15超级启动N-803的效果（McBrien，Nature 2020）。这些研究共同揭示了 在抗病毒本质的情况下，CD8+淋巴细胞的先前未识别的功能 可能会矛盾地利用具有集成，复制能力的CD4+ T细胞的长期持久性 病毒。如果进一步确认，这一假设将在设计艾滋病毒的角度上具有深远的影响。 并基于调节CD8+ T细胞的潜伏活性而杀死”策略 可以促进已重新激活病毒产生的CD4+ T细胞消亡的药物。 该提案的总体目的是更好地了解基于 去除CD8+淋巴细胞以破坏SIV/SHIV持久性，并降低甚至消除病毒效果 在艺术下。我们将基于我们先前发布的数据，并使用高度相关，良好验证的模型 恒河猕猴（RM）的SIV/SHIV感染，回答三个重要问题：（i）什么是细胞 以及在经ART治疗的SIV感染中观察到的鲁棒和持续病毒重新激活的解剖学来源 与CD8α耗竭和N-803合并处理后的RMS？ （AIM＃1）; （ii）我们可以清除CD4+ T细胞 CD8α或CD8β耗竭 + N-803在ART-中给予病毒产生的病毒产生 通过用ENV特异性的广泛中和的鸡尾酒处理动物，处理了Shiv感染的RMS 抗体（bnabs）？ （AIM＃2）; （iii）我们可以影响已重新激活病毒的CD4+ T细胞的凋亡 CD8α耗竭 + N-803在ART处理的SHIV感染的RMS中产生的生产。 具有抗凋亡分子Bcl-2的抑制剂的动物？ （AIM＃3）。 我们很毒 耶克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，相信我们将能够提供有关如何促进活动的新颖，关键的信息 可以在体内操纵CD8+淋巴细胞，以减少ART下的持续性病毒储量。