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CD8 T cell suppression of HIV latency establishment and maintenance in virally suppressed individuals

CD8 T 细胞抑制病毒抑制个体中 HIV 潜伏期的建立和维持

基本信息

批准号：
10459483
负责人：
Deanna A Kulpa
金额：
$ 39万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459483
关键词：
Address Animals CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Clinical Clinical Research Cytotoxic T-Lymphocytes DNA Modification Process Disease Epigenetic Process Excision Flow Cytometry Future Gene Expression Genetic Transcription Goals HIV HIV Infections Histone Deacetylation In Vitro Individual Infection Interleukin-15 Interruption Intervention Laboratories Lead Longevity Lymphocyte Suppression Macaca Maintenance Mediating Methylation Modeling Molecular Outcome Phenotype Play Predisposition Production Role SIV Series Shock T-Lymphocyte Subsets Testing Therapeutic Transcript Viral Viral reservoir Viremia Virus Virus Replication Work antiretroviral therapy base combinatorial cytokine design effective intervention experimental study high dimensionality histone methylation improved in vitro Model in vivo innovation novel novel strategies transcription factor viral rebound viral rescue

项目摘要

ABSTRACT: Current antiretroviral therapy (ART) does not eradicate HIV as shown by the rapid rebound of viremia upon treatment interruption. Rescuing viral gene expression in latently infected cells by compounds termed Latency Reversing Agents (LRA) is a strategy to reduce the virus reservoir in ART-treated HIV-infected individuals (i.e., shock & kill). HIV latency is triggered by mechanisms that lead to the silencing of virus expression including epigenetic DNA modification through histone methylation and deacetylation, limited availability of critical transcription factors and inefficient elongation of the nascent viral transcripts. Recent studies in ART-treated SIV- infected macaques demonstrated that depletion of CD8+ lymphocytes is followed by reactivation of virus production, and increased susceptibility to the LRA effect of the IL-15 superagonist ALT803. These results strongly suggest that CD8+ lymphocyte play an important yet understudied role in silencing HIV expression. In this proposal, we hypothesize that CD8+ T cells suppress HIV gene expression by promoting the establishment and maintenance of HIV latency, and that reversal of this effect may result in a significant amplification of the LRA effect of various compounds, thus impacting the reservoir size and stability in vivo. We will use innovative approaches to identify the CD8+ T cell mediated mechanisms of HIV silencing. In Aim 1, we will employ a novel model of HIV latency to characterize the role of CD8+ T cells in the establishment of HIV latency. We will quantify HIV gene expression in CD4+ T cell subsets and characterize the impact of CD8+ T cells on HIV latency establishment. In Aim 2, we will characterize the role of CD8+ T cells in the maintenance of HIV latency. Our in vitro model will allow us to define how CD8+ T cells maintain HIV latency during cytokine driven activation, proliferation or differentiation. In Aim 3, we will design a combinatorial anti-latency strategy that will eliminate most if not all latently infected cells. We will employ high dimensional flow cytometry to define alterations in phenotype associated with suppression and activation of latency reversal. Ultimately, we will characterize the role of CD8+ lymphocyte in counter-acting the latency reversal by specific LRAs (and LRA combinations) as a key step to develop effective interventions in which viral transcription in latently infected cells is rescued to reduce the reservoir size. The experiments described in this proposal will identify novel mechanisms of HIV silencing that can lead to the reactivation and subsequent elimination of most (if not all) latently infected cells. We propose that this overarching goal can be achieved through a step-wise scientific approach that includes in vitro and ex vivo studies that will address a newly-defined mechanism of HIV persistence. We believe that the work proposed in this application will allow us to understand the mechanisms by which CD8+ lymphocytes suppress virus transcription and ultimately promote HIV latency and persistence in ART-treated HIV-infected individuals, thus helping designing new approaches for HIV eradication.

摘要：目前的抗逆转录病毒疗法(Art)并不能根除HIV，正如病毒血症迅速反弹所表明的那样。治疗中断。潜伏期化合物挽救潜伏感染细胞中病毒基因的表达逆转剂(LRA)是一种减少经ART治疗的HIV感染者中的病毒库的策略(即，电击和杀戮)。HIV潜伏期由导致病毒表达沉默的机制触发，包括通过组蛋白甲基化和去乙酰化进行表观遗传DNA修饰，关键药物的有限可用性转录因子和新生病毒转录本的低效延长。抗逆转录病毒治疗SIV的最新研究- 感染的猕猴表明，CD8+淋巴细胞耗尽之后是病毒的重新激活产生，并增加对IL-15超级激动剂ALT803的LRA效应的敏感性。这些结果强烈建议CD8+淋巴细胞在抑制HIV表达方面发挥重要作用，但尚未得到充分研究。在这个方案中，我们假设CD8+T细胞通过促进HIV基因的表达来抑制HIV基因的表达建立和维持艾滋病毒潜伏期，扭转这一影响可能导致显著放大各种化合物的LRA效应，从而影响体内储存库的大小和稳定性。我们将使用创新的方法来确定CD8+T细胞介导的HIV沉默机制。在目标1中，我们将使用一种新的HIV潜伏期模型来表征CD8+T细胞在HIV建立中的作用延迟。我们将量化HIV基因在CD4+T细胞亚群中的表达，并表征CD8+T细胞的影响细胞对HIV潜伏期的建立。在目标2中，我们将描述CD8+T细胞在维持艾滋病毒潜伏期。我们的体外模型将允许我们定义CD8+T细胞如何在细胞因子期间维持HIV潜伏期驱动激活、增殖或分化。在目标3中，我们将设计一种组合反延迟策略将消除大部分(如果不是全部)潜伏感染细胞。我们将使用高维流式细胞术来确定与潜伏期逆转抑制和激活相关的表型改变。最终，我们会 CD8+淋巴细胞在对抗特定LRA(和LRA)逆转潜伏期中的作用组合)作为开发有效干预措施的关键一步，在该干预措施中，潜伏感染细胞中的病毒转录被抢救出来，以缩小水库的规模。这项提案中描述的实验将确定新的机制可导致大多数(如果不是全部)潜伏感染的艾滋病毒重新激活和随后消除的艾滋病毒沉默细胞。我们建议，这一总体目标可以通过循序渐进的科学方法来实现包括体外和体外研究，这些研究将解决艾滋病毒持续存在的新定义的机制。我们相信这项申请中提出的工作将使我们能够理解CD8+ 在ART治疗中，淋巴细胞抑制病毒转录并最终促进HIV潜伏期和持久性艾滋病毒感染者，从而帮助设计根除艾滋病毒的新方法。