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主要在静息状态下以潜伏状态持续存在 CD 4 + T细胞。靶向HIV-1包膜蛋白的中和和非中和抗体（nNAb）均可 通过自然杀伤细胞（NK）的抗体依赖性细胞毒性（ADCC）介导感染细胞的杀伤 细胞或巨噬细胞和其它吞噬细胞的抗体依赖性细胞吞噬作用（ADCP）。因为艺术 不直接杀死HIV-1感染的细胞，抗体可以在消除残留病毒中发挥重要作用。 水库广泛反应的中和抗体（bNAb），可以中和广泛的临床HIV-1， 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 对抗体介导的病毒抑制很重要。此外，Fc片段对于抗体是不可缺少的- 由于其与先天效应细胞上的Fc受体（FcR）接合，因此可介导细胞杀伤。重要的是 评估抗体在组织中的效力，特别是在淋巴组织中，因为它们是HIV的主要部位- 1感染，是HIV-1最重要的解剖学储存库。先天性组织的细胞杀伤功能 效应细胞对于抗体治疗效果是至关重要的。我们比较了人类扁桃体和淋巴中的NK细胞 淋巴结与外周血中的NK细胞进行比较，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，因为：1）它们不表达Fc-γ受体IIIA（CD 16 a）; 2） 它们产生非常少的细胞溶解分子如颗粒酶B和穿孔素。该补助金的目的是 研究如何使用人体组织活检来改善Fc依赖性效应细胞清除HIV-1储库的功能 和人源化小鼠模型。我们的目标是：1）开发新的方法来提高ADCP活性; 2） 改善淋巴组织中NK细胞成熟以获得ADCC活性。我们的研究将提供关键的 对基于抗体的HIV治疗研究的影响。

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.