封闭免疫检查点NKG2A增强NK和T细胞介导的细胞毒效应以清除HIV-1潜伏感染的研究

“激活-杀灭”是研究最为广泛的一种HIV-1功能性治愈策略。近年来NKG2A被认为是一种新型的抑制性免疫检查点受体。封闭NKG2A具备同时激活NK细胞和T细胞的独特优势，在免疫治疗中显示出巨大的应用潜力，但其免疫增强效应的潜在机制还需清晰阐述及其在抗HIV中的应用价值尚未明确。本项目将深入探讨NKG2A阻断剂增强NK细胞和T细胞通过抗体依赖性或抗体非依赖性途径免疫激活的潜在机制，并阐明NKG2A阻断后NK细胞和T细胞效应之间存在的协同促进作用。最后从HIV感染的独特性出发，在深入分析NKG2A封闭后，HIV不同感染类型人群NK细胞、CD8+T细胞以及CD56+T细胞免疫应答特征和效应变化的基础上，探讨应用NKG2A阻断剂联合“激活-杀灭”策略，通过诱导强烈的抗病毒免疫应答达到缩小甚至清除HIV病毒储存库的可行性。本研究可为HIV/AIDS功能性治愈优化方案提供新的思路和手段。

“Shock and kill” strategy is one of the most widely discussed approaches of “functional cure” for eliminating the HIV-1 latent reservoir. Recently, NKG2A is identified as a novel inhibitory immune checkpoint. Blocking NKG2A showed great potential for application in immunotherapy by promoting immune responses mediated by both natural killer (NK) and T cells, but the potential mechanisms of its immune enhancement effect have not been clearly elucidated and its application values in anti-HIV therapy have not been clearly defined. In this study, we will explore the potential mechanisms of NKG2A blocking agent to enhance immune activation of NK cells and T cells via antibody-dependent or antibody-independent pathways, and elucidate possible synergistic effect of NK cells and T cells triggered by NKG2A blockade. Finally, in view of the uniqueness of HIV infection, on the basis of analyzing immune characteristics and functions of CD56+ NK cells, CD8+ T cells and CD56+ T cells from individuals with different HIV clinical status induced by NKG2A blockade, we will explore the feasibility of contracting and even eradicating HIV-1 latent reservoir via intense anti-viral immune responses triggered by NKG2A blocking agent in combination with “shock and kill” strategy. This work will provide new suggestion for developing novel strategies of “functional cure” of HIV/AIDS.