High-Definition Characterization of the Persistence and Perturbation of the HIV Reservoir: Project 3

摘要 SAR441236是一种三特异性HIV-1广谱中和抗体(BNab)，它结合了 VRC01-LS的CD4结合位点(CD4bs)特异性、V1/V2糖链介导的结合 PGDM1400和10E8v4的gp41MPER结合成一个抗体分子(1)。这 三特异性bNab比任何单一的bNab具有更大的效力和广度，并提供完整的 混合SHIV保护猕猴免受直肠内攻击。 与三个单独的单一种属相比，三合一的bNab的优势 联合使用bNAbs有可能提高疗效并简化预防 和治疗方案，可能会提高患者的依从性。ACTG A5377是第一阶段的第一阶段- SAR441236的人体研究，研究了这种新的三特异性bNab在病毒学和 携带艾滋病毒的无菌血症参与者。 注射HIV-1bNab可能通过两种途径影响储集层动态 机制：1)清除残留病毒粒子和受感染细胞的直接抗病毒作用，和/或2) 间接作用，改善抗艾滋病毒监测和免疫功能。科学的前提是 这项建议的目的是在抑制感染期间使用SAR441236进行选择性治疗 修剪HIV-1前病毒格局，直接或间接影响免疫系统功能， 加强对HIV-1的控制。这项提案的目标是确定三特异性bNab 抑制ART期间的治疗影响HIV-1前病毒景观，并定义 如果有的话，三特异性bNab给药对免疫系统和抗HIV的影响 免疫反应。 我们假设SAR441236导致完整前病毒变体的选择性丧失， 调节Treg和抗原提呈细胞(APC)功能，提高细胞免疫功能 对HIV-1的反应。这项提案的具体目的是调查SAR441236的遴选 HIV-1储存库的压力，确定SAR441236对外周免疫的影响 单细胞分辨率的系统表观基因组、转录组和细胞表面蛋白质组，以及 了解SAR441236对细胞免疫应答-CD8T细胞和NK细胞的影响 细胞--以提高水库的清除能力。我们的方法建立在新技术的基础上进行测试 以前未曾探索过的假说，这些假说对于理解如何治疗 SAR441236影响HIV-1前病毒宿主和外周免疫系统。

Abstract SAR441236 is a tri-specific HIV-1 broadly neutralizing antibody (bnAb) that combines the CD4 binding site (CD4bs) specificity of VRC01-LS, the V1/V2 glycan-directed binding of PGDM1400, and the gp41 MPER binding of 10E8v4 into one antibody molecule (1). This trispecific bnAb has greater potency and breadth than any single bnAb and provided complete protection to macaques against intra-rectal challenge by a mixture of SHIVs. The advantages of a three-in-one bnAb, when compared to three separate monospecific bnAbs administered in combination, are the potential to improve efficacy and simplify prevention and treatment regimens, possibly improving patient adherence. ACTG A5377 is a phase I first- in-human study of SAR441236 that investigates this novel trispecific bnAb in viremic and aviremic participants with HIV. Administration of an HIV-1 bnAb could affect reservoir dynamics through two mechanisms: 1) a direct antiviral effect that clears residual virions and infected cells, and/or 2) indirect effects that improve anti-HIV surveillance and immune function. The scientific premise of this proposal is that treatment with SAR441236 during suppressed infection selectively prunes the HIV-1 proviral landscape and affects immune system function, directly or indirectly, to improve HIV-1 control. The goals of this proposal are to determine if trispecific bnAb treatment during suppressive ART impacts the HIV-1 provirus landscape and to define what effects, if any, trispecific bnAb administration has on the immune system and the anti-HIV immune response. We hypothesize that SAR441236 leads to the selective loss of intact provirus variants, modulates Treg and antigen presenting cell (APC) function, and improves cytolytic immune responses to HIV-1. Specific Aims of this proposal are to investigate SAR441236 selection pressure on the HIV-1 reservoir, define the effects of SAR441236 on the peripheral immune system epigenome, transcriptome and cell surface proteome at single cell resolution, and to understand the effects of SAR441236 on cytolytic immune responses – CD8+ T cells and NK cells - to enhance reservoir clearance. Our approaches build on novel technologies to test previously unexplored hypotheses that are central to understand how treatment with SAR441236 influences the HIV-1 proviral reservoir and the peripheral immune system.