Assessing ADCC and Fc-mediated Protection against HIV

评估 ADCC 和 Fc 介导的 HIV 保护作用

• 批准号: 10671615
• 负责人: David T Evans
• 金额: $ 76.71万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-13 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671615
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Agreement; Animal Model; Animals; Antibodies; Antibody Response; Antibody Specificity; Antibody-Dependent Enhancement; Antibody-mediated protection; Binding; Biological Assay; Cells; Collaborations; Consensus; Correlative Study; Dose; Epitopes; Evaluation; Exposure to; Fc Receptor; Fc domain; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Immune response; Immunotherapy; Infection; Infection prevention; Intravenous infusion procedures; Investigation; Ligands; Macaca; Macaca mulatta; Measurement; Measures; Mediating; Methods; Modeling; Molecular; Molecular Conformation; Mucous Membrane; Outcome; Passive Transfer of Immunity; Patients; Physiological; Polysaccharides; Predisposition; Primates; Research; Risk; Specificity; Standardization; Stress; Testing; Thailand; Uncertainty; Vaccines; Variant; Viral; Virus; antibody test; antibody-dependent cell cytotoxicity; design; high throughput screening; improved; innovation; insight; model design; nef Protein; nonhuman primate; novel strategies; response; simian human immunodeficiency virus; transmission process; vaccine discovery; vaccine trial; vpu Protein

PROJECT SUMMARY Efforts to develop an effective vaccine against HIV-1/AIDS continue to be hampered by an incomplete understanding of the immune responses needed for protection. Non-neutralizing antibody functions, such as the elimination of virus-infected cells by antibody-dependent cellular cytotoxicity (ADCC), are widely believed to have contributed to the reduced risk of HIV-1 infection among vaccine recipients in the RV144 trial; however, the antibody specificities and effector functions underlying this protection have not been clearly defined. This uncertainty can be attributed in part to differences in methods for measuring ADCC, a limited understanding of the factors influencing the sensitivity of HIV-infected cells to antibodies, and a lack of definitive evidence for protection by non-neutralizing antibodies in animal models. Although correlative evidence suggests that antibodies to variable 1 and 2 (V1V2) region and CD4-inducible (CD4i) epitopes of HIV-1 gp120 may have contributed to protection, this has been difficult to confirm experimentally. The proposed studies will therefore take advantage of the combined expertise of our research team to improve methods for measuring ADCC and to test the antibody specificities and effector functions implicated in the outcome of the RV144 trial in a nonhuman primate model. In Aim 1, we will determine the impact of viral and cellular factors that modulate the sensitivity of HIV-infected cells to antibodies on methods for measuring ADCC. In Aim 2, we will develop and implement a high-throughput assay platform to enable a comprehensive assessment of ADCC directed against distinct conformations of the HIV-1 envelope glycoprotein. In Aim 3, we will test the hypothesis that V1V2- and/or CD4i-specific antibodies can afford partial protection in a low-dose mucosal SHIV challenge model designed to simulate conditions of HIV-1 CRF01_AE transmission in Thailand, where the RV144 trial took place. In Aim 4, we will test Fc domain variants of V1V2- and CD4i-specific antibodies for the ability to protect macaques against low-dose mucosal SHIV challenge to determine the extent to which Fc-mediated effector functions may contribute to protection. These unprecedented studies are expected to reveal fundamental molecular mechanisms that influence the sensitivity of HIV-infected cells to antibodies and their implications for measuring ADCC, provide a standardizable, high-throughput assay for quantifying ADCC as a correlate of protection, and yield greater insight into the types of antibody responses that may ultimately be needed for protection against HIV-1.

项目概要 开发有效的 HIV-1/AIDS 疫苗的努力仍然受到不完整的阻碍。 了解保护所需的免疫反应。非中和抗体功能，例如 人们普遍认为，通过抗体依赖性细胞毒性（ADCC）消除病毒感染的细胞 在 RV144 试验中有助于降低疫苗接种者感染 HIV-1 的风险；然而， 这种保护作用背后的抗体特异性和效应器功能尚未明确定义。这 不确定性部分归因于测量 ADCC 的方法的差异，以及对 ADCC 的有限理解。 影响HIV感染细胞对抗体敏感性的因素，缺乏明确的证据 动物模型中非中和抗体的保护作用。尽管相关证据表明 HIV-1 gp120 可变区 1 和 2 (V1V2) 区和 CD4 诱导型 (CD4i) 表位的抗体可能具有 有助于保护，但这很难通过实验证实。因此，拟议的研究将 利用我们研究团队的综合专业知识来改进 ADCC 的测量方法和 测试与 RV144 试验结果相关的抗体特异性和效应器功能 非人类灵长类动物模型。在目标 1 中，我们将确定调节病毒和细胞因素的影响 HIV 感染细胞对 ADCC 测量方法中抗体的敏感性。在目标 2 中，我们将开发并 实施高通量检测平台，以针对 ADCC 进行全面评估 HIV-1 包膜糖蛋白的独特构象。在目标 3 中，我们将检验假设 V1V2- 和/或 CD4i 特异性抗体可以在低剂量粘膜 SHIV 攻击模型中提供部分保护 旨在模拟泰国的 HIV-1 CRF01_AE 传播条件，RV144 试验在泰国进行 地方。在目标 4 中，我们将测试 V1V2 和 CD4i 特异性抗体的 Fc 结构域变体的保护能力 猕猴对抗低剂量粘膜 SHIV 攻击以确定 Fc 介导的效应子的程度 功能可能有助于保护。这些史无前例的研究有望揭示基本原理 影响 HIV 感染细胞对抗体敏感性的分子机制及其影响 测量 ADCC，提供标准化的高通量测定，用于量化 ADCC 作为相关性 保护，并更深入地了解最终可能需要的抗体反应类型 预防 HIV-1。