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的策略需要结构知识，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。直到最近，针对HIV-1的少数广泛中和抗体（BNAB）的特征是其广度和效能的免疫学基础仍然很少了解。全面了解抗体如何中和艾滋病毒的一个重要障碍是单克隆bnabs的供应有限。通过从产生高滴定广泛中和活性的患者的B细胞中的HIV抗体分离的新方法解决了这个问题。 Michel Nussenzweig博士最近分离的几种抗体，包括NIH45-46、3bnc117和3bnc60，显示出比以前最好的BNAB的VRC01相比的效力和宽度。我们最近解决了与GP120结合的NIH45-46的结构，并使用基于结构的设计将其效力提高至少10倍，这使得NIH45-46G54W成为当前可用的最有效的抗HIV BNAB。我们将与Nussenzweig博士合作，以确定新bnab的可变晶圆厂与新捐助者隔离的宽敞和有效中和的结构相关性。 BNAB抗HIV功效的基本知识将促进对自然人类单克隆抗体的广度和效力进行优化，以通过免疫或基因疗法被动递送，并提供开发会引起BNABS的主动免疫策略所需的基本框架。将追求以下特定目的：1）求解BNAB Fabs和BNAB Fab-GP120复合物的晶体结构，以定义广泛而有效的HIV中和的基本特征。 2）产生自然抗体变异体，具有中和活性增强。 公共卫生相关性：艾滋病毒/艾滋病仍然是当前对全球公共卫生的最重要威胁之一。至少有6000万人感染了艾滋病毒，其中几乎一半死亡。尽管抗逆转录病毒药物在发达国家有效，但在发展中国家迫切需要一种防止感染的疫苗和/或新方法。我们将系统地分析新的抗HIV抗体，以了解其保护机制并改善被动递送预防策略的抗体。