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

摘要 SAR 441236是一种三特异性HIV-1广泛中和抗体（bnAb）， VRC 01-LS的CD 4结合位点（CD 4 bs）特异性，V1/V2聚糖定向结合 PGDM 1400和10 E8 v4的gp 41 MPER结合成一个抗体分子（1）。这 三特异性bnAb具有比任何单一bnAb更大的效力和广度，并且提供了完整的 保护猕猴免受SHIV混合物的直肠内攻击。 与三种单独的单特异性抗体相比，三合一bnAb的优势 bnAb联合给药有可能提高疗效并简化预防 和治疗方案，可能提高患者的依从性。ACTG A5377是第一阶段- 研究这种新型三特异性bnAb在病毒血症和 艾滋病病毒感染者。 给予HIV-1 bnAb可能通过两个途径影响储库动力学 机制：1）清除残留病毒体和感染细胞的直接抗病毒作用，和/或2） 间接影响，提高抗艾滋病毒监测和免疫功能。科学前提 该建议的一个重要方面是，在抑制感染期间选择性地使用SAR 441236治疗 修剪HIV-1前病毒景观并直接或间接地影响免疫系统功能， 改善HIV-1控制。本提案的目标是确定三特异性bnAb是否 在抑制性ART期间的治疗影响HIV-1前病毒景观，并确定 三特异性bnAb给药对免疫系统和抗HIV抗体的影响（如果有的话） 免疫反应 我们假设SAR 441236导致完整前病毒变体的选择性丢失， 调节Treg和抗原呈递细胞（APC）功能，并改善溶细胞免疫 对HIV-1的反应。本提案的具体目的是研究SAR 441236选择 对HIV-1储库的压力，确定SAR 441236对外周免疫的影响 系统表观基因组、转录组和细胞表面蛋白质组， 了解SAR 441236对溶细胞免疫应答-CD 8 + T细胞和NK的影响 细胞-以提高水库清除。我们的方法建立在新技术的基础上， 以前未探索的假设是核心，以了解如何治疗与 SAR 441236影响HIV-1前病毒储库和外周免疫系统。

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.