B and T Cell Biology of Protection from and Eradication of SIV/SHIV Infection - Administrative Supplement

摘要 埃默里非人灵长类艾滋病创新研究联盟旨在了解B和T 预防和根除SIV/SIV感染的细胞生物学。该财团高度团结在一起 在一系列艾滋病毒疫苗和治疗学科中合作、富有成效的研究人员，以解决 最重要的假设是，成功的预防性艾滋病毒疫苗将需要强大和持续的系统性 粘膜免疫应答，由功能性靶向抗体和组织驻留CD8 T细胞组成 免疫，与调节的HIV特异性CD4T细胞反应相一致，维持低数量的HIV 粘膜组织中的靶点，同时为强烈的适应性反应提供足够的帮助。此外，我们假设 在新型活性潜伏期反转剂的背景下，免疫调节方法可以直接杀死 通过抗病毒抗体重新激活的细胞和对凋亡的敏感性增加将减少病毒库 从而在抗逆转录病毒药物停止后保持对病毒复制的抑制。这些方法 在以下目的的重点1中总结的是将利用与本地三聚环境相结合的最先进的佐剂 诱导和机械地剖析强烈的持久体液反应的免疫原。此外，我们的目标是 充分表征和利用一种新的组织驻留CD8T细胞群，以有效地与 体液免疫反应在提供对异种SIV攻击的保护中。在焦点2中，我们将利用 新型潜伏期反转剂和CD8+T细胞耗尽，以定义最佳的重新激活程序，然后 我将把这些与抗病毒的单抗和bcl2的抑制剂结合起来，以探索这种 联合使用可在停用购物车后持续抑制病毒复制。这些实验性的 方法将得到5个最先进的科学研究支持核心的支持，以充分描述 体液反应的大小、功能、特异性和谱系。单细胞分析和 转录学还将支持在细胞水平上表征先天和适应性信号。这 这一综合计划的补充申请有两个具体目标。在目标1(焦点1)中，我们将 测试功能性抗体反应和组织驻留T细胞在提供长期免疫方面的协同作用 对异源第2层阴道内分支C-SHV挑战的保护。在目标2(焦点2)中，我们将测试 一种抗SIV单抗的鸡尾酒和体外显示的化合物ventoclax的组合 使储存细胞对凋亡敏感，有助于减少病毒储存在设置中的病毒潜伏期的有效逆转。 这些研究的结果将对开发有效的预防性疫苗具有重要意义。 以及艾滋病毒的治疗策略。

ABSTRACT The Emory Consortium for Innovative AIDS Research in Nonhuman Primates aims to understand the B and T cell biology of protection from and eradication of SIV/SHIV infection. The consortium brings together highly collaborative, and productive investigators in a range of HIV vaccine and cure disciplines to address the overarching hypothesis that a successful prophylactic HIV vaccine will require a strong and sustained systemic and mucosal immune response, comprised of functionally targeted antibody and tissue resident CD8 T cell immunity, in concert with a modulated HIV-specific CD4 T cell response that maintains low numbers of HIV targets in mucosal tissue, while providing adequate help for a strong adaptive response. Moreover, we postulate that in the context of novel active latency reversing agents, immunomodulatory approaches to directly kill reactivated cells through antiviral antibodies and increased sensitivity to apoptosis will reduce viral reservoirs and thus maintain suppression of virus replication following cessation of anti-retroviral drugs. The approaches summarized in FOCUS 1 of the aims below will utilize state of the art adjuvants coupled with native trimeric Env immunogens to induce and mechanistically dissect strong durable humoral responses. In addition, we aim to fully characterize and harness a novel population of tissue resident CD8 T cells to effectively synergize with the humoral immune response in providing protection from heterologous SHIV challenge. In FOCUS 2 we will utilize novel latency reversing agents and CD8+ T cell depletion to define an optimal reactivation program, and then will combine these with the antiviral monoclonal antibodies and inhibitors of BCL-2 to explore the potential of this combination to yield a sustained suppression of virus replication following cART withdrawal. These experimental approaches will be supported by 5 state of the art Scientific Research Support Cores in order to fully characterize the magnitude, function, specificity and repertoire of the humoral response. Single cell analytics and transcriptomics will also support characterization of innate and adaptive signals at the cellular level. This supplement application for this comprehensive program has two specific aims. In Aim 1 (FOCUS 1), we will test the synergy between functional antibody response and tissue resident T cells in providing long-term protection against a heterologous tier-2 intravaginal clade C SHIV challenge. In Aim 2 (FOCUS 2), we will test if a combination of a cocktail of anti-SIV monoclonal antibodies and a compound, venetoclax, shown in vitro to sensitize reservoir cells to apoptosis help to reduce viral reservoirs in the setting of potent reversal of viral latency. Results from these studies will have important implications for the development of effective preventive vaccines and cure strategies for HIV.