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: 9924483
• 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/9924483
• 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; Phagocytosis; Phase; Plasma; Preventive vaccine; Proteins; Research; Resistance; Risk; SIV; Site; Somatic Mutation; Testing; V3 Loop; Vaccination; Vaccines; Virion; Virus; Virus Diseases; antibody-dependent cell cytotoxicity; 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

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.

项目总结/摘要 免疫效应机制，赋予对艾滋病毒感染的保护仍然知之甚少。 初免/加强ALVAC+ gp 120蛋白疫苗的III期RV 144试验的免疫相关性分析， 这提供了一个整体减少31.2%的艾滋病毒感染，表明在抗gp 120的保护潜力， 抗体反应。具体而言，在RV 144病例中评价的6个主要免疫学参数中- 在对照研究中，对HIV包膜（Env）gp 120的V1 V2环的高IgG应答与HIV-1感染显著相关。 降低感染艾滋病毒的风险。这种保护的相关性在SIV/猕猴中得到了重现 模型此外，在中和抗体和Env特异性血浆水平较低的疫苗接种者亚组中， 伊加、对V3环的抗体应答和介导抗体依赖性细胞毒性的抗体 （ADCC）也与保护有关。然而，目前还不清楚这些V1 V2和V3是否以及如何， 特异性抗体直接介导其保护作用。这些抗体没有广泛的中和作用， 活性，但靶向V1 V2和V3环的保守区域，并能够介导Fc依赖性 体外抗病毒功能。针对保守构象表位的非中和抗体也 协同增强ADCC活性。我们在此建议调查保护潜力， 靶向V1 V2、V3和其他类似免疫原性保守Env的抗体的作用机制 通过在人源化小鼠（hu-100）中测试被动施用的人单克隆抗体（mAb）， 小鼠）模型。该研究基于我们的初步发现，即非中和性V1 V2 mAb和 弱中和性V3 mAb各自能够降低hu-mice中的病毒感染率和/或病毒负荷， 用CD 34+人造血干细胞移植并用2级JRFL HIV-1病毒攻击。 这些和其他可通过疫苗接种诱导的抗Env抗体赋予针对Env的保护作用的程度是确定的。 不同的HIV-1病毒株尚未确定，它们的抗病毒机制也尚未确定。 因此，我们提出了实验，首先，评估抗V1 V2和抗V3人mAb的能力， 在用HIV-1分离株，特别是经传播/创始人感染的HIV-1分离株攻击后，保护hu小鼠免受病毒感染 来自亚型B和C的病毒。第二，我们建议测试疫苗诱导的人单克隆抗体， 使用相同的mAb转移/病毒攻击，在hu-mice中Env的V3和恒定区中的表位 approach.第三，我们将研究这些mAb在保护免受HIV感染方面的Fab和Fc贡献。到 为此，我们将测量mAb靶向游离病毒体和感染细胞（包括离体病毒体）的能力 和来自病毒感染的Hu小鼠的细胞。我们还将制备具有Fc突变的mAb，其废除或 增强Fc-受体相互作用并测试它们保护hu-小鼠对抗病毒攻击的能力。数据从该 拟议的研究将帮助我们了解抗体的类型和免疫原性Env表位，由于 它们的保护潜力，应在未来的艾滋病毒疫苗开发中加以考虑。