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: 10401312
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10401312
• 关键词: AIDS/HIV problem; ALVAC; Animals; Antibodies; Antibody Response; Antibody-Dependent Enhancement; 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; Vaccinee; 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.

项目概要/摘要 对于防止艾滋病毒感染的免疫效应机制仍知之甚少。 初免/加强 ALVAC+gp120 蛋白疫苗 III 期 RV144 试验的免疫相关分析， HIV 感染总体减少了 31.2%，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： 对照研究显示，对 HIV 包膜 (Env) gp120 的 V1V2 环的高 IgG 反应与 降低感染艾滋病毒的风险。此后，这种保护的相关性在 SIV/猕猴中得到了重述 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。然而，目前尚不清楚这些 V1V2- 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 V1V2 和 V3 环的保守区域，并且能够介导 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 协同增强 ADCC 活性。我们在此建议调查保护潜力和 针对 V1V2、V3 和其他具有类似免疫原性的保守 Env 的抗体的作用机制 通过在人源化小鼠（hu- 小鼠）模型。拟议的研究基于我们的初步发现，即非中和性 V1V2 mAb 和 弱中和 V3 mAb 均能够降低 hu-mice 的病毒感染率和/或病毒负荷， 被植入 CD34+ 人类造血干细胞并受到 2 级 JRFL HIV-1 病毒的攻击。 这些抗体和其他可通过疫苗接种诱导的抗 Env 抗体在多大程度上提供了针对 不同的HIV-1毒株尚未确定，其抗病毒机制也尚未确定。 因此，我们提出实验，首先评估抗 V1V2 和抗 V3 人单克隆抗体的能力 在受到 HIV-1 分离株攻击后，保护 hu-mice 免受病毒感染，特别是传播/创始人 来自 B 和 C 亚型的病毒。其次，我们建议测试疫苗诱导的人类单克隆抗体针对保守的 使用相同的 mAb 转移/病毒攻击，检测 hu-小鼠 V3 和 Env 恒定区的表位 方法。第三，我们将研究这些 mAb 在预防 HIV 方面的 Fab 和 Fc 贡献。到 为此，我们将测量 mAb 靶向游离病毒粒子和受感染细胞（包括离体病毒粒子）的能力 以及体外感染病毒的腐殖质小鼠的细胞。我们还将制备具有 Fc 突变的 mAb，这些突变可消除或 增强 Fc 受体相互作用并测试其保护 hu-mice 免受病毒攻击的能力。数据来自于此 拟议的研究将帮助我们了解抗体和免疫原性 Env 表位的类型，由于 在未来的艾滋病毒疫苗开发中应考虑它们的保护潜力。

项目成果

Immune profiles to distinguish hospitalized versus ambulatory COVID-19 cases in older patients.

• DOI: 10.1016/j.isci.2022.105608
• 发表时间: 2022-12-22
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Klingler, Jeromine;Lambert, Gregory S.;Bandres, Juan C.;Emami-Gorizi, Rozita;Nadas, Arthur;Oguntuyo, Kasopefoluwa Y.;Amanat, Fatima;Bermudez-Gonzalez, Maria C.;Gleason, Charles;Kleiner, Giulio;Simon, Viviana;Lee, Benhur;Zolla-Pazner, Susan;Upadhyay, Chitra;Hioe, Catarina E.
• 通讯作者: Hioe, Catarina E.

Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice.

• DOI: 10.1371/journal.ppat.1010183
• 发表时间: 2022-01
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Hioe CE;Li G;Liu X;Tsahouridis O;He X;Funaki M;Klingler J;Tang AF;Feyznezhad R;Heindel DW;Wang XH;Spencer DA;Hu G;Satija N;Prévost J;Finzi A;Hessell AJ;Wang S;Lu S;Chen BK;Zolla-Pazner S;Upadhyay C;Alvarez R;Su L
• 通讯作者: Su L

A tale of four studies: HIV vaccine immunogenicity and efficacy in clinical trials.

• DOI: 10.1016/s2352-3018(21)00073-4
• 发表时间: 2021-07
• 期刊: The lancet. HIV
• 作者: Zolla-Pazner S;Michael NL;Kim JH
• 通讯作者: Kim JH