Harnessing Highly Networked HLA-E-Restricted CTL Epitopes to Achieve a Broadly Effective HIV Cure

利用高度网络化的 HLA-E 限制性 CTL 表位实现广泛有效的 HIV 治愈

• 批准号: 10684371
• 负责人: Gaurav Das Gaiha
• 金额: $ 116.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684371
• 关键词: Adherence; Alleles; Animals; Antigens; Award; Cytotoxic T-Lymphocytes; Data; Development; Doctor of Medicine; Epidemic; Epitopes; General Hospitals; Genes; HIV; HIV vaccine; Human; Individual; Knock-in; Knowledge; Life; Massachusetts; Medicine; Methodology; Mission; Mus; National Institute of Drug Abuse; Nature; Pathway Analysis; Population; Proteome; Research; Structure; T cell response; T-Lymphocyte Epitopes; Testing; Therapeutic; Translations; United States National Institutes of Health; Vaccination; Vaccines; Work; drug of abuse; immunogenicity; innovation; medical schools; novel; novel vaccines; professor; protein structure; rational design; resistance mutation; theories; vaccine candidate

ABSTRACT This proposal describes the framework of an Avant-Garde DP1 award for Dr. Gaurav Gaiha M.D. D.Phil. Dr. Gaiha is currently an Assistant Professor of Medicine at Harvard Medical School, Massachusetts General Hospital and the Ragon Institute of MGH, Harvard and MIT. Dr. Gaiha’s research is focused on leveraging an innovative approach known as structure-based network analysis towards the development of a functional HIV cure. This new methodology developed by Dr. Gaiha integrates network theory principles with protein structure data to identify mutation-resistant cytotoxic T cell (CTL) epitopes within the HIV proteome. These ‘highly networked’ epitopes were found to be preferentially targeted by individuals who naturally control HIV in the absence of therapy, setting the stage for translation of these findings into an effective, CTL-based vaccine for HIV. However, a major challenge to the development of a broad CTL-based vaccine is the highly polymorphic nature of MHC-Ia alleles (HLA A/B/C allomorphs) within the population at-large. Thus, this proposal intends to generate and test a vaccine candidate comprised of highly networked CTL epitopes restricted by the non- classical MHC-Ib HLA-E molecule, which is highly conserved among humans with only two known alleles. Our analyses of the HIV proteome have already identified five highly networked, HLA-E restricted HIV epitopes. To evaluate whether these epitopes can be harnessed into a novel vaccine, this proposal first seeks to leverage a novel mono-allelic HLA-E mouse developed using an innovative gene knock-in methodology. These animals will then be injected with a diverse set of multi-epitope immunogens comprised of HLA-E-restricted highly networked epitopes and assessed for the induction of de novo CTL responses in the presence and absence of drugs of abuse. The development of such a vaccine would have a major impact on the HIV epidemic as it would be broadly applicable to substance abusing populations who have reduced adherence and provide an economically feasible approach to achieve a functional HIV cure. Demonstrating the immunogenicity of a multi-networked HLA-E restricted epitope vaccine aims to overcome the obstacles associated with traditional approaches to therapeutic HIV vaccination and is consistent with the mission of both NIDA and the broader mission of the NIH.

抽象的 该提案描述了 Gaurav Gaiha 博士（医学博士、哲学博士）的前卫 DP1 奖项的框架。 Gaiha 目前是马萨诸塞州哈佛医学院的医学助理教授 Gaiha 博士的研究重点是利用麻省总医院、哈佛大学和麻省理工学院的 Ragon 研究所。 称为基于结构的网络分析的创新方法，用于开发功能性艾滋病毒 Gaiha 博士开发的这种新方法将网络理论原理与蛋白质结构相结合。 这些数据可用于识别 HIV 蛋白质组中的抗突变细胞毒性 T 细胞 (CTL) 表位。 发现“网络化”表位是自然控制艾滋病毒的个体的优先目标。 缺乏治疗，为将这些发现转化为有效的、基于 CTL 的疫苗奠定了基础 然而，开发基于 CTL 的广泛疫苗的一个主要挑战是高度多态性。 总体人群中 MHC-Ia 等位基因（HLA A/B/C 同种异形体）的性质 因此，该提案旨在 生成并测试由高度网络化的 CTL 表位组成的候选疫苗，这些表位受非 经典的 MHC-Ib HLA-E 分子，在人类中高度保守，只有两个已知的等位基因。 HIV 蛋白质组分析已经确定了五个高度网络化的 HLA-E 限制性 HIV 表位。 评估这些表位是否可以用于新型疫苗，该提案首先寻求利用 使用创新的基因敲入方法开发的新型单等位基因 HLA-E 小鼠这些动物将。 然后注射由 HLA-E 限制性高度网络化的多种多表位免疫原组成 表位并评估在存在或不存在药物的情况下诱导从头 CTL 反应 这种疫苗的开发将对艾滋病毒的流行产生重大影响。 广泛适用于药物滥用人群，他们的依从性有所下降，并提供经济上的帮助 实现功能性艾滋病毒治愈的可行方法，展示多网络的免疫原性。 HLA-E 限制性表位疫苗旨在克服与传统方法相关的障碍 HIV 疫苗接种符合 NIDA 的治疗使命以及 NIH 的更广泛使命。