Assessing ADCC and Fc-mediated Protection against HIV

评估 ADCC 和 Fc 介导的 HIV 保护作用

• 批准号: 10808458
• 负责人: David T Evans
• 金额: $ 18.56万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10808458
• 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.

项目摘要 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 通过抗体依赖性细胞毒性（ADCC）消除病毒感染的细胞，被广泛认为 在RV 144试验中，有助于降低疫苗接种者感染HIV-1的风险;然而， 这种保护作用所依据的抗体特异性和效应子功能尚未明确定义。这 不确定性可以部分归因于测量ADCC的方法的差异， 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， 在动物模型中通过非中和抗体进行保护。尽管相关证据表明， 针对HIV-1 gp 120的可变区1和2（V1 V2）区和CD 4诱导型（CD 4 i）表位的抗体可能具有 虽然有助于保护，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，改进测量ADCC的方法， 为了测试RV 144试验结果中涉及的抗体特异性和效应子功能， 非人类灵长类动物模型在目标1中，我们将确定调节细胞增殖的病毒和细胞因子的影响。 HIV感染细胞对抗体的敏感性对测量ADCC的方法的影响。在目标2中，我们将开发和 实施高通量分析平台，以实现针对ADCC的全面评估 HIV-1包膜糖蛋白的不同构象。在目标3中，我们将测试V1 V2- 和/或CD 4 i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， 地方在目标4中，我们将测试V1 V2-和CD 4 i-特异性抗体的Fc结构域变体保护CD 4 i的能力。 猕猴对抗低剂量粘膜SHIV攻击，以确定Fc介导的效应物 功能可能有助于保护。这些前所未有的研究有望揭示 影响HIV感染细胞对抗体敏感性的分子机制及其对 测量ADCC，提供了一种用于定量ADCC的可重复的高通量测定法， 保护，并产生更深入的了解类型的抗体反应，可能最终需要 预防HIV-1。

项目成果

HIV-1 Vpu Downregulates Tim-3 from the Surface of Infected CD4+ T Cells.

HIV-1 Vpu 下调受感染 CD4 T 细胞表面的 Tim-3。

• DOI: 10.1128/jvi.01999-19
• 发表时间: 2020
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Prévost,Jérémie;Edgar,CassandraR;Richard,Jonathan;Trothen,StevenM;Jacob,RajeshAbraham;Mumby,MitchellJ;Pickering,Suzanne;Dubé,Mathieu;Kaufmann,DanielE;Kirchhoff,Frank;Neil,StuartJD;Finzi,Andrés;Dikeakos,JimmyD
• 通讯作者: Dikeakos,JimmyD