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 该建议描述了Gaurav Gaiha M.D. D.Phil博士的前卫DP1奖的框架。博士 Gaiha目前是马萨诸塞州哈佛医学院医学助理教授 医院和MGH，哈佛大学和麻省理工学院的Ragon研究所。 Gaiha博士的研究重点是利用 创新方法称为基于结构的网络分析，用于开发功能HIV 治愈。 Gaiha博士综合网络理论与蛋白质结构开发的新方法 数据以鉴定HIV蛋白质组中耐突变的细胞毒性T细胞（CTL）表位。这些高度 发现网络的表位是由自然控制艾滋病毒在 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 艾滋病病毒。但是，开发基于CTL的疫苗的主要挑战是高度多态性的 MHC-IA等位基因（HLA A/b/c异形）的性质很大。那，该提议打算 生成并测试候选疫苗的候选疫苗，该疫苗由非限制的高度网络CTL表位 经典的MHC-Ib HLA-E分子，在只有两个已知等位基因的人类中，它是高度保守的。我们的 HIV蛋白质组的分析已经确定了五个高度网络的HLA-E受限HIV表位。到 评估这些表位是否可以利用为新型疫苗，该提议首先试图利用 新型的单相关HLA-E小鼠使用创新的基因敲击方法开发。这些动物会 然后注入多种多样的HLA-E限制性高度网络的多种诊断免疫原 表位，并评估在存在和不存在药物的情况下诱导从头ctl反应 虐待。这种疫苗的开发将对艾滋病毒流行产生重大影响，因为 广泛适用于滥用滥用种群的物质，这些人群降低了依从性并在经济上提供 实现功能性HIV治疗的可行方法。证明多网络的免疫原性 HLA-E受限的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，与NIDA和NIH更广泛的任务的任务一致。