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.

摘要 本提案描述了授予Gaurav Gaiha M.D.Phil博士的先锋DP1奖的框架。Dr。 盖哈目前是马萨诸塞州总医院哈佛医学院的医学助理教授 以及麻省理工学院、哈佛大学和麻省理工学院拉贡研究所。盖哈博士的研究重点是利用 一种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 解药。Gaiha博士开发的这一新方法将网络理论原理与蛋白质结构相结合 识别HIV蛋白质组中耐突变细胞毒性T细胞(CTL)表位的数据。这些都是高度 研究发现，网络表位优先被自然控制艾滋病毒的人作为靶标 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 爱滋病毒。然而，发展广泛的基于CTL的疫苗的一个主要挑战是高度多态 MHC-Ia等位基因(HLAA/B/C同型)在一般人群中的性质。因此，这项提案打算 生成和测试由高度联网的CTL表位组成的候选疫苗，该表位受非 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。我们的 对HIV蛋白质组的分析已经确定了五个高度网络化的、人类白细胞抗原E限制性的HIV表位。至 评估这些表位是否可以被利用到新的疫苗中，这项提议首先寻求利用 使用创新的基因敲入方法开发的新的单等位基因人类白细胞抗原-E小鼠。这些动物会 然后注射一组由高度联网的人类白细胞抗原E限制的多表位免疫原组成的多样化的多表位免疫原 表位及其在药物存在和不存在时诱导从头CTL反应的评估 虐待。这种疫苗的开发将对艾滋病毒流行产生重大影响 广泛适用于依从性降低并在经济上提供 实现功能性艾滋病毒治愈的可行方法。展示多网络疫苗的免疫原性 人类白细胞抗原E限制性表位疫苗旨在克服与传统方法相关的障碍 治疗性艾滋病毒疫苗接种，符合NIDA的使命和NIH更广泛的使命。