Novel Strategies to Enhance Effector Cell Functions for Antibody-Mediated Clearance of HIV-1 Infection

摘要 在接受抑制性抗逆转录病毒治疗(ART)的患者中，HIV-1主要在休息时保持潜伏状态。 CD4+T细胞。针对HIV-1囊膜蛋白的中和抗体和非中和抗体都可以 自然杀伤细胞(NK)通过抗体依赖性细胞毒(ADCC)介导对感染细胞的杀伤作用 巨噬细胞和其他吞噬细胞的抗体依赖性细胞吞噬作用(ADCP)。既然艺术 不会直接杀死感染HIV-1的细胞，抗体可以在消除残留病毒方面发挥重要作用 水库。广谱反应性中和抗体(BNAbs)，可中和广泛的临床艾滋病毒- 1分离株给HIV治疗研究带来了新的希望。越来越多的证据表明，Fc片段是 对抗体介导的病毒抑制很重要。此外，Fc片段是抗体不可缺少的- 由于其与先天效应细胞上的Fcr受体结合而介导细胞杀伤。这很重要 评估组织中的抗体效力，特别是淋巴组织，因为它们是艾滋病毒的主要部位- 1感染，是HIV-1最重要的解剖储存库。组织先天的细胞杀伤功能 效应细胞是抗体治疗效果的关键。我们比较了人类扁桃体或淋巴中的NK细胞 发现淋巴组织中的绝大多数NK细胞是 不成熟和缺乏ADCC活性的原因是：1)不表达Fc-γ受体IIIA(CD16A)； 它们产生非常少的细胞溶解分子，如颗粒酶B和穿孔素。这笔赠款的目的是 利用人体组织活检研究如何改善Fc依赖的效应细胞功能以清除HIV-1储存库 和人性化的老鼠模型。我们的目标是：1)开发增强ADCP活性的新方法；2) 促进淋巴组织中NK细胞的成熟，以获得ADCC活性。我们的研究将提供关键的 对以抗体为基础的艾滋病毒治疗研究的启示。

Abstract In patients under suppressive antiretroviral therapy (ART), HIV-1 persists in a latent state primarily in resting CD4+ T cells. Both neutralizing and non-neutralizing antibodies (nNAbs) targeting HIV-1 envelop protein can mediate killing of infected cells through antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells or antibody-dependent cellular phagocytosis (ADCP) by macrophages and other phagocytes. Since ART does not directly kill HIV-1-infected cells, antibodies can play an important role in elimination of the residual viral reservoirs. Broadly reactive neutralizing antibodies (bNAbs) that could neutralize a wide spectrum of clinical HIV- 1 isolates brought new hope to HIV cure research. There is burgeoning evidence that the Fc fragment is important to the antibody-mediated viral suppression. Moreover, the Fc fragment is indispensable for antibody- mediated cell killing because of its engagement with Fc-receptors (FcR) on the innate effector cells. It is important to evaluate antibody efficacy in tissues, especially in lymphoid tissues, because they are the major sites for HIV- 1 infection and are the most important anatomical reservoirs for HIV-1. The cell-killing functions of tissue innate effector cells are critical to antibody therapeutic effects. We compared NK cells from human tonsils or lymph nodes with those from peripheral blood, and found that vast majority of the NK cells in lymphoid tissues are immature and deficient in ADCC activity because:1) they do not express Fc-gamma receptor IIIA (CD16a); 2) they produce very little cytolytic molecules such as granzyme B and perforin. The objective of this grant is to study how to improve Fc-dependent effector cell functions to clear HIV-1 reservoirs using human tissue biopsies and humanized mouse models. We aim to: 1) develop the novel approaches to enhance ADCP activity; 2) improve maturation of NK cells in lymphoid tissues to acquire ADCC activity. Our study will provide critical implications to antibody-based HIV cure research.