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 广泛中和抗体 (bnAb)，结合了 VRC01-LS 的 CD4 结合位点 (CD4bs) 特异性、V1/V2 聚糖定向结合 PGDM1400 和 10E8v4 的 gp41 MPER 结合成一个抗体分子 (1)。这个 三特异性 bnAb 比任何单一 bnAb 具有更大的效力和广度，并提供完整的 保护猕猴免受直肠内 SHIV 混合物的攻击。 与三个单独的单特异性抗体相比，三合一 bnAb 的优势 bnAb 联合使用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 I 期首个 SAR441236 的人体研究，研究了这种新型三特异性 bnAb 在病毒血症和 患有艾滋病毒的无病毒血症参与者。 HIV-1 bnAb 的给药可能通过以下两种方式影响病毒库动态： 机制：1) 直接抗病毒作用，清除残留的病毒粒子和受感染的细胞，和/或 2) 改善抗艾滋病毒监测和免疫功能的间接影响。科学前提 该提案的重点是在抑制感染期间选择性地使用 SAR441236 进行治疗 修剪 HIV-1 前病毒环境并直接或间接影响免疫系统功能， 改善 HIV-1 控制。该提案的目标是确定三特异性 bnAb 是否 抑制性 ART 期间的治疗会影响 HIV-1 原病毒状况并确定什么 三特异性 bnAb 给药对免疫系统和抗 HIV 药物的影响（如果有的话） 免疫反应。 我们假设 SAR441236 导致完整原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。该提案的具体目标是调查 SAR441236 选择 HIV-1 储存库的压力，定义 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，并 了解 SAR441236 对溶细胞免疫反应 – CD8 T 细胞和 NK 的影响 细胞 - 增强储层清除能力。我们的方法建立在新技术的基础上进行测试 以前未探索过的假设对于理解如何治疗至关重要 SAR441236 影响 HIV-1 前病毒库和外周免疫系统。

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.