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

摘要 该提案描述了Gaurav Gaiha博士的前卫DP 1奖的框架。D.Phil.博士 Gaiha目前是马萨诸塞州综合医院哈佛医学院的医学助理教授 医院和MGH，哈佛和麻省理工学院的Ragon研究所。Gaiha博士的研究重点是利用 一种创新的方法，称为基于结构的网络分析，用于开发功能性HIV 疗方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 鉴定HIV蛋白质组中抗突变细胞毒性T细胞（CTL）表位的数据。这些“高度 发现“网络”表位优先被自然控制HIV的个体靶向， 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。然而，开发广泛的基于CTL的疫苗的主要挑战是高度多态性的CTL。 MHC-Ia等位基因（HLA A/B/C同种异型）在人群中的性质。因此，本提案旨在 产生并测试由非免疫原性限制的高度网络化的CTL表位组成的疫苗候选物， 经典的MHC-Ib HLA-E分子，其在人类中高度保守，只有两个已知的等位基因。我们 对HIV蛋白质组的分析已经鉴定出五个高度网络化的HLA-E限制性HIV表位。到 评估这些表位是否可以利用到一种新的疫苗中，这项建议首先寻求利用一种 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 表位，并在存在和不存在以下药物的情况下评估从头CTL应答的诱导： 虐待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，这些人群的依从性降低， 一种可行的方法来实现艾滋病毒的功能性治愈。证明多网络免疫原性 HLA-E限制性表位疫苗旨在克服与传统方法相关的障碍， 治疗性HIV疫苗接种，并且与NIDA的使命和NIH的更广泛的使命一致。

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.