Structural Basis of Antibody-Mediated Neutralization of HIV

抗体介导的 HIV 中和的结构基础

• 批准号: 8467311
• 负责人: Pamela J Bjorkman
• 金额: --
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2012-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467311
• 关键词: AIDS Vaccines; AIDS/HIV problem; Abbreviations; Active Immunization; Affinity; African; Anti-Retroviral Agents; Antibodies; B-Lymphocytes; Binding; Binding Sites; Biological Assay; Bispecific Antibodies; Cells; Child; Collaborations; Complementarity Determining Regions; Complex; Crystallization; Exhibits; Fc Receptor; Framework Regions; Goals; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV envelope protein; HIV-1; Highly Active Antiretroviral Therapy; Immune system; Immunization; Immunoglobulin G; Immunology; In Vitro; Individual; Infection prevention; Injection of therapeutic agent; Knowledge; Laboratories; Light; Liquid substance; Mediating; Methods; Modeling; Mothers; Mutagenesis; Mutation; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Point Mutation; Prevention strategy; Proteins; Public Health; Reagent; Reporting; Resistance; Robot; Structure; Techniques; Vaccines; Variant; Viral; Virus; X ray diffraction analysis; X-Ray Diffraction; antibody-dependent cell cytotoxicity; antigen binding; arm; base; combat; design; directed evolution; gene therapy; human monoclonal antibodies; improved; neutralizing antibody; passive antibodies; prevent; protein expression; resistant strain; structural biology; synchrotron radiation

DESCRIPTION (provided by applicant): Strategies to combat HIV-1 require structural knowledge of how antibodies recognize HIV envelope proteins and how they are used by the immune system to eliminate viruses and virally-infected cells. Until recently, only a small number of broadly neutralizing antibodies (bNAbs) against HIV-1 had been characterized and the immunological basis for their breadth and potency remains poorly understood. One important obstacle to a comprehensive understanding of how antibodies neutralize HIV was the limited availability of monoclonal bNAbs. This issue was resolved by new methods for HIV antibody isolation from B cells of patients who produce high titers of broad neutralizing activity. Several of the antibodies recently isolated by Dr. Michel Nussenzweig's laboratory, including NIH45-46, 3BNC117 and 3BNC60, show superior potency and breadth to VRC01, previously the best bNAb. We recently solved the structure of NIH45-46 bound to gp120, and used structure-based design to increase its potency by at least 10-fold, making NIH45-46G54W the most potent anti- HIV bNAb currently available. We will collaborate with Dr. Nussenzweig to determine the structural correlates of broad and potent neutralization by the variable Fabs of new bNAbs as they are isolated from new donors. Basic knowledge of bNAb efficacy against HIV will facilitate optimization of the breadth and potency of natural human monoclonal antibodies for passive delivery by immunization or gene therapy and provide to the underlying framework needed to develop active immunization strategies that will elicit bNAbs. The following specific aims will be pursued: 1) Solve crystal structures of bNAb Fabs and bNAb Fab-gp120 complexes to define the essential features of broad and potent HIV neutralization. 2) Produce natural antibody variants with enhanced activity in neutralization. PUBLIC HEALTH RELEVANCE: HIV/AIDS remains one of the most important current threats to global public health. At least 60 million people have been infected with HIV, of which almost half have died. Although anti-retroviral drugs have been effective in the developed world, a vaccine and/or new methods to prevent infections are urgently needed in the developing world. We will systematically analyze new anti-HIV antibodies with goals of understanding their protective mechanisms and improving antibodies for passive delivery prevention strategies.

描述（由申请人提供）：对抗 HIV-1 的策略需要了解抗体如何识别 HIV 包膜蛋白以及免疫系统如何使用它们来消除病毒和病毒感染的细胞的结构知识。直到最近，只有少数针对 HIV-1 的广泛中和抗体 (bNAb) 得到了表征，并且其广度和效力的免疫学基础仍然知之甚少。全面了解抗体如何中和 HIV 的一个重要障碍是单克隆 bNAb 的可用性有限。这个问题通过从患者的 B 细胞中分离出 HIV 抗体的新方法得到了解决，这些抗体产生高滴度的广泛中和活性。 Michel Nussenzweig 博士实验室最近分离出的几种抗体，包括 NIH45-46、3BNC117 和 3BNC60，显示出优于 VRC01（之前最好的 bNAb）的效力和广度。我们最近解决了 NIH45-46 与 gp120 结合的结构，并使用基于结构的设计将其效力提高了至少 10 倍，使 NIH45-46G54W 成为目前可用的最有效的抗 HIV bNAb。我们将与 Nussenzweig 博士合作，确定从新供体中分离出的新 bNAb 的可变 Fab 所产生的广泛而有效的中和作用的结构相关性。 bNAb 抗 HIV 功效的基础知识将有助于优化天然人单克隆抗体的广度和效力，用于通过免疫或基因治疗被动递送，并提供开发引发 bNAb 的主动免疫策略所需的基础框架。我们将追求以下具体目标： 1) 解析 bNAb Fab 和 bNAb Fab-gp120 复合物的晶体结构，以确定广泛且有效的 HIV 中和的基本特征。 2) 产生中和活性增强的天然抗体变体。 公共卫生相关性：艾滋病毒/艾滋病仍然是当前全球公共卫生面临的最重要威胁之一。至少有 6000 万人感染了艾滋病毒，其中近一半人死亡。尽管抗逆转录病毒药物在发达国家已经有效，但发展中国家迫切需要疫苗和/或预防感染的新方法。我们将系统地分析新的抗艾滋病毒抗体，目的是了解其保护机制并改进被动分娩预防策略的抗体。