Assessing ADCC and Fc-mediated Protection against HIV

评估 ADCC 和 Fc 介导的 HIV 保护作用

• 批准号: 10458659
• 负责人: David T Evans
• 金额: $ 76.76万
• 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/10458659
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Agreement; Animal Model; Animals; Antibodies; Antibody Response; Antibody Specificity; Antibody-Dependent Enhancement; Antibody-mediated protection; Biological Assay; Cells; 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; base; design; high throughput screening; improved; innovation; insight; model design; nef Protein; nonhuman primate; novel strategies; receptor binding; 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.

项目总结 开发有效的艾滋病毒-1/艾滋病疫苗的努力继续受到不完整的 了解保护所需的免疫反应。非中和抗体功能，如 通过抗体依赖的细胞毒性(ADCC)消除病毒感染的细胞，被广泛认为是 有助于降低RV144试验中疫苗接受者感染HIV-1的风险；然而， 这种保护背后的抗体特异性和效应器功能还没有明确的定义。这 不确定性可以部分归因于测量ADCC的方法的不同，对ADCC的理解有限 影响HIV感染细胞对抗体敏感性的因素，以及缺乏明确的证据 动物模型中非中和抗体的保护作用。尽管相关证据表明 抗HIV-1gp120可变区1和2(V1V2)区和可诱导CD4(CD4i)表位的抗体可能具有 尽管这有助于保护，但这很难在实验上得到证实。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衡量ADCC和 为了测试RV144试验结果中所涉及的抗体特异性和效应器功能 非人灵长类动物模型。在目标1中，我们将确定病毒和细胞因素的影响，这些因素调节 人类免疫缺陷病毒感染细胞对抗体敏感性的研究在目标2中，我们将发展和 实施高通量检测平台，以便针对以下方面对ADCC进行全面评估 HIV-1包膜糖蛋白的不同构象。在目标3中，我们将检验假设V1V2- 和/或CD4i特异性抗体可在低剂量黏膜SIV攻击模型中提供部分保护 旨在模拟HIV-1 CRF01_AE在泰国的传播条件，RV144试验在泰国进行 地点。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 猕猴对低剂量黏膜SIV攻击确定Fc介导的效应器的程度 功能可能有助于保护。这些史无前例的研究有望揭示 影响HIV感染细胞对抗体敏感性的分子机制及其对 ADCC的测定，提供了一种标准化的、高通量的测定ADCC的方法 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感染。