Harnessing Abs specific for immunogenic and conserved Env epitopes to protect against HIV

利用免疫原性和保守的 Env 表位特异性抗体来预防 HIV

• 批准号: 10153678
• 负责人: Catarina E Hioe
• 金额: $ 81.34万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-07 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153678
• 关键词: AIDS/HIV problem; ALVAC; Animals; Antibodies; Antibody Response; Antibody-Dependent Enhancement; Antiviral Agents; Blood; CD34 gene; Case-Control Studies; Cells; Data; Development; Epitopes; Face; Fc Receptor; Future; Genes; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Hematopoietic stem cells; Human; Immune; Immunoglobulin A; Immunoglobulin Constant Region; Immunoglobulin G; Immunologics; In Vitro; Individual; Infection; Lymphoid Tissue; Macaca; Measures; Mediating; Modeling; Molecular Conformation; Monoclonal Antibodies; Mus; Mutation; Passive Transfer of Immunity; Patients; Phase; Plasma; Preventive vaccine; Proteins; Research; Resistance; Risk; SIV; Site; Somatic Mutation; Testing; V3 Loop; Vaccination; Vaccines; Virion; Virus; Virus Diseases; antibody transfer; antibody-dependent cell cytotoxicity; antibody-dependent cellular phagocytosis; base; complementarity-determining region 3; cytotoxicity; design; experimental study; human monoclonal antibodies; humanized mouse; immunogenic; in vivo; infection rate; infection risk; mouse model; neutralizing antibody; pandemic disease; protective effect; response; success; transmission process; vaccine development; vaccine evaluation; vaccine trial; vaccine-induced antibodies

Project Summary/Abstract Immune effector mechanisms that confer protection against HIV acquisition remain poorly understood. Immune-correlates analysis of the Phase III RV144 trial of the prime/boost ALVAC+gp120 protein vaccine, which delivered an overall 31.2% reduction in HIV acquisition, suggested a protective potential in anti-gp120 antibody responses. Specifically, of the 6 primary immunologic parameters evaluated in the RV144 case- control study, high IgG responses to the V1V2 loop of HIV envelope (Env) gp120 significantly correlated with a reduced risk of HIV acquisition. This correlate of protection has since been recapitulated in the SIV/macaque model. Moreover, in a subset of vaccinees with lower levels of neutralizing antibodies and Env-specific plasma IgA, antibody responses to the V3 loop and antibodies mediating antibody-dependent cellular cytotoxicity (ADCC) were also associated with protection. However, it remains unclear if and how these V1V2- and V3- specific antibodies directly mediate their protective effects. These antibodies have no broad neutralizing activity, but target conserved regions of the V1V2 and V3 loops and are capable of mediating Fc-dependent antiviral functions in vitro. Nonneutralizing antibodies against conserved conformational epitopes also synergize to enhance ADCC activity. We propose herein to investigate the protective potential and mechanisms of action of antibodies targeting V1V2, V3, and other, similarly immunogenic, conserved Env epitopes by testing passively administered human monoclonal antibodies (mAbs) in a humanized mouse (hu- mice) model. The proposed study is based on our preliminary findings that a nonneutralizing V1V2 mAb and a weakly neutralizing V3 mAb were each able to reduce virus infection rate and/or virus burden in hu-mice that were engrafted with CD34+ human hematopoietic stem cells and challenged with a tier 2 JRFL HIV-1 virus. The extent to which these and other anti-Env antibodies inducible by vaccination confer protection against diverse HIV-1 strains has not been determined, and their antiviral mechanisms also have not been defined. Therefore, we propose experiments to, first, evaluate the ability of anti-V1V2 and anti-V3 human mAbs to protect against virus infection in hu-mice upon challenge with HIV-1 isolates, particularly transmitted/founder viruses from subtypes B and C. Second, we propose testing vaccine-induced human mAbs against conserved epitopes in the V3 and constant regions of Env in hu-mice, using the same mAb transfer/virus challenge approach. Third, we will investigate the Fab and Fc contributions of these mAbs in protection against HIV. To this end, we will measure the mAb capacity to target free virions and infected cells, including ex vivo virions and cells from virus-infected hu-mice, in vitro. We will also prepare mAbs with Fc mutations that abrogate or enhance Fc-receptor interactions and test their ability to protect hu-mice against virus challenge. Data from this proposed study will help us understand the types of antibodies and immunogenic Env epitopes that, due to their protective potential, should be considered in future HIV vaccine development.

项目摘要/摘要 赋予对HIV获取保护的保护的免疫效应机制仍然很众所周知。 对质量/增强ALVAC+GP120蛋白疫苗的III期RV144期试验的免疫相关分析， 这使艾滋病毒收购的总体降低了31.2％，这表明抗GP120具有保护潜力 抗体反应。具体而言，在RV144病例中评估的6个主要免疫学参数中 对照研究，对HIV包膜（Env）GP120的V1V2环路的高IgG响应与A显着相关 降低了艾滋病毒收购风险。此后，这种保护的相关性已在SIV/猕猴中概括 模型。此外，在中和抗体和ENV特异性等离子体水平较低的疫苗中 IgA，对V3环的抗体反应和介导抗体依赖性细胞毒性的抗体 （ADCC）也与保护有关。但是，尚不清楚这些V1V2-和V3-是否以及如何 特定抗体直接介导其保护作用。这些抗体没有广泛的中和 活性，但是V1V2和V3环的目标保守区域，能够介导FC依赖性 体外抗病毒功能。对抗构象表位的非中和抗体也 协同作用以增强ADCC活性。我们在此提议调查保护潜力和 靶向V1V2，V3和其他类似免疫原性的抗体作用机理 通过在人源化小鼠中测试被动施用人类单克隆抗体（mAb）的表位（hu-- 小鼠）模型。拟议的研究基于我们的初步发现，即非中和化V1V2 mAb和a 弱中和的V3 mAb每个人都能够降低HU-MICE中的病毒感染率和/或病毒负担 被CD34+人类造血干细胞植入，并用2级JRFL HIV-1病毒挑战。 这些和其他抗ENV抗体可通过疫苗接种诱导的保护范围 尚未确定不同的HIV-1菌株，并且尚未定义其抗病毒机制。 因此，我们提出实验首先评估抗V1V2和抗V3人物mAb的能力 在使用HIV-1分离株（特别是传播/创始人）挑战时，防止HU小鼠中的病毒感染 亚型B和C的病毒。其次，我们提出了测试疫苗诱导的人物mAb对保守的 使用相同的mAb转移/病毒挑战，在HU-MICE的V3和ENV的恒定区域中的表位 方法。第三，我们将调查这些mAB在保护艾滋病毒中的FAB和FC贡献。到 这一目的，我们将测量靶向自由病毒体和感染细胞的单元单元能力，包括离体病毒体 来自病毒感染的HU小鼠的细胞，体外。我们还将准备用消除或 增强FC受体相互作用，并测试其保护HU-MICE免受病毒挑战的能力。来自此的数据 拟议的研究将帮助我们了解由于 它们的保护潜力应在未来的HIV疫苗开发中考虑。