Mechanisms of Natural Killer Cell Clearance of SIV from Lymphoid Follicles

尽管CART有效地抑制了HIV感染患者的血浆病毒血症，但复制能力强 病毒仍然可以从各种解剖部位恢复。艾滋病毒和致病性SIV感染的主要宿主 恒河猴(RM)的淋巴滤泡(通过在TFH细胞中复制和FDC捕获病毒) 一般禁止接触细胞毒性CD8 T细胞。有趣的是，非洲绿的非致病性SIV感染 猴(AGM)在血液和肠道粘膜中表现出高病毒载量，但在淋巴滤泡中缺乏病毒。 自然杀伤(NK)细胞提供对艾滋病毒/SIV感染的快速早期反应，并在很大程度上有助于 疾病调控和疫苗保护，但NK细胞监测和疫苗保护的潜在机制 艾滋病毒/SIV宿主的调节尚不清楚。我们最近的研究表明，SIV可以有效地清除 来自非致病性AGM而非致病性RM宿主的淋巴滤泡，并依赖于IL-15- NK细胞对淋巴滤泡的依赖性再分布和AGM-NK上CXCR5表达的增加 (Huot et al.自然医学2017年)。在这个创新的提案中，我们将利用三个感染SIV的非人类 灵长类动物模型检验NK细胞对SIV减少起关键作用的中心假设 水库。具体地说，我们将：(1)确定与NK细胞介导的 SIV水库；以及(2)确定与NK细胞失效有关的机制以控制SIV水库 在淋巴结及相关发病机制中的作用。这些数据的应用可以大大有助于 未来的HIV/SIV疫苗、免疫疗法或利用有效抗病毒的水库清除策略 NK细胞的潜能。

Despite efficient suppression of plasma viremia in HIV-infected patients on cART, replication competent virus is still recoverable from a variety of anatomic sites. A major reservoir of HIV and pathogenic SIV infection in rhesus macaques (RM) are lymph node follicles (via replication in TFH cells and viral trapping by FDC) that generally prohibit access to cytotoxic CD8+ T cells. Interestingly, nonpathogenic SIV infection of African green monkeys (AGM) exhibits high viral loads in blood and the gut mucosae, but lacks virus in lymphoid follicles. Natural killer (NK) cells provide rapid early responses to HIV/SIV infections and contribute substantially to disease modulation and vaccine protection, but the underlying mechanisms for NK cell surveillance and modulation of HIV/SIV reservoirs is unclear. Our recent research indicates that SIV can be effectively cleared from lymphoid follicles in nonpathogenic AGM but not pathogenic RM hosts and is dependent on an IL-15- dependent redistribution of NK cells to lymph node follicles and increased CXCR5 expression on AGM NK (Huot et al. Nature Medicine 2017). In this innovative proposal we will utilize three SIV-infected nonhuman primate models to test the central hypothesis that NK cells critically contribute to the reduction of SIV reservoirs. Specifically we will: (1) Determine mechanisms associated with NK cell-mediated control of SIV reservoirs; and (2) Determine mechanisms associated with NK cell failure to control SIV reservoirs in lymph nodes and associated pathogenesis. Application of these data could contribute substantially to future HIV/SIV vaccines, immunotherapeutics, or reservoir purging strategies that harness the potent antiviral potential of NK cells.