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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：
10654784
负责人：
ATHE M. TSIBRIS
金额：
$ 48.63万
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/10654784
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