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

HIV 病毒库的持续性和扰动的高清表征：项目 3

基本信息

批准号：
10469113
负责人：
ATHE M. TSIBRIS
金额：
$ 47.16万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10469113
关键词：
AIDS clinical trial group Affect Animal Model Antibodies Antibody Therapy Antigen-Presenting Cells Attention Binding Binding Sites Biology CD8-Positive T-Lymphocytes Cell physiology Cell surface Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Clinical DNA Dendritic cell activation Detection Disease remission Dose Enrollment Equilibrium Evolution FCGR3B gene Fab domain Fc domain Goals HIV HIV-1 Half-Life IgG Receptors IgG1 Immune Immune response Immune system Immunity Immunotherapeutic agent Individual Infection Infusion procedures Length Macaca Maintenance Malignant Neoplasms Mediating Modification Monoclonal Antibodies Natural Killer Cells Participant Peripheral Phase Phenotype Phylogeny Placebos Polysaccharides Population Prevention Process Production Proteins Proteome Proviruses RNA Regulatory T-Lymphocyte Residual state Resolution Role Sampling Serum Specificity T cell response T-Lymphocyte Techniques Testing Therapeutic Intervention Therapeutic Monoclonal Antibodies Time Tissues Treatment Protocols Vaccines Variant Viral Viral Proteins Viral reservoir Viremia Virion Virus Work antibody-dependent cell cytotoxicity antigen binding antiretroviral therapy cohort compliance behavior cytotoxic CD8 T cells design epigenome first-in-human follow-up human study immune function immune system function improved in vivo multimodality neonatal Fc receptor neutralizing antibody new technology novel novel therapeutics peripheral blood pressure receptor expression response simian human immunodeficiency virus single cell analysis transcriptome

项目摘要

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.

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。