Leveraging CTLs targeting highly networked epitopes to suppress the latent HIV-1 reservoir

利用针对高度网络化表位的 CTL 来抑制潜在的 HIV-1 病毒库

基本信息

批准号：
9906843
负责人：
Gaurav Das Gaiha
金额：
$ 19.98万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-05 至 2020-09-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906843
关键词：
AIDS/HIV problem Address Adenovirus Vector Alleles Area Biochemistry CD4 Positive T Lymphocytes Career Mobility Cells Chronic Clinical Trials Clone Cells Coculture Techniques Conserved Sequence Cytotoxic T-Lymphocytes DNA Development Drug resistance Drug toxicity Elements Epidemic Epitopes Fellowship Gastroenterology General Hospitals HIV HIV vaccine HIV-1 Human Immunize Immunology Individual Institutes Knowledge Life Link Massachusetts Mediating Medical Medicine Mentors Methods Mission Modality Mus Mutagenesis Mutate Mutation Network-based Pathway Analysis Patients Physicians Positioning Attribute Problem Solving Program Development Progressive Disease Proteome Public Health Research Rest Scientist Site Structure T cell response T-Lymphocyte Epitopes Testing Therapeutic Transgenes Transgenic Mice Translations United States National Institutes of Health Vaccines Viral Viral reservoir Viremia Virus Walkers Work antiretroviral therapy base career development cell mediated immune response cost design economic implication experience experimental study fitness in vivo individual response insight instructor latent HIV reservoir medical schools medication compliance mutation screening novel strategies prevent prophylactic protein structure response skills structured data targeted treatment theories therapeutic vaccine therapy duration treatment duration vaccine candidate vaccinology viral fitness viral rebound

项目摘要

Project Summary/Abstract This proposal presents a five year research career development program focused on the study of CTL responses to highly “networked” epitopes as a new set of invariant targets to include in a therapeutic CTL- based vaccine for HIV-1. The candidate is currently an Instructor of Medicine at Harvard Medical School and the Division of Gastroenterology at Massachusetts General Hospital. The outlined proposal builds on the candidate's previous research experience in HIV-1 immunology and biochemistry where he defined CTL epitopes that carry structural and functional constraints, and which are preferentially targeted by individuals who naturally control HIV-1. He is now positioned, under the guidance of his mentor Dr. Bruce Walker at the Ragon Institute of MGH, MIT and Harvard, to determine whether these epitopes could be valuable CTL targets in treatment-suppressed individuals. The proposed experiments and didactic work will position the candidate with a unique set of skills that will enable him transition to independence as a physician-scientist in the field of prophylactic and therapeutic HIV-1 vaccinology. The HIV/AIDS epidemic continues to have enormous medical, societal and economic implications worldwide. While combination anti-retroviral therapy (cART) has helped to greatly reduce the global burden of HIV, the ability of the virus to establish a persistent latent reservoir requires lifelong treatment for HIV-infected individuals. As a result, new modalities that can suppress or eliminate the viral reservoir and thereby limit HIV treatment duration are greatly needed. Recent efforts have been focused on the induction of cytotoxic T cells as potential targets for therapeutic vaccines. However, the accumulation of CTL escape mutations in chronically infected cART-suppressed patients limits the ability to successfully prevent viral rebound following cART cessation. During his postdoctoral fellowship, the candidate developed a new approach known as structure-based network analysis that identifies specific epitopes, presented by a broad array of HLA alleles, which are intolerant to mutations. He also demonstrated that the targeting of highly “networked” CTL epitopes is able to distinguish individuals who spontaneously control HIV-1 from those with progressive disease. The candidate now hypothesizes that CTL mediated immune responses directed against highly “networked” epitopes can also suppress viral outgrowth following cART cessation in chronically infected cART-treated individuals. This hypothesis will be tested through the following aims: 1) Perform deep mutational scanning of highly networked epitopes in proviral DNA, 2) Assess whether CTLs targeting highly networked epitopes can suppress viral outgrowth from cART-treated patients and 3) Develop an adenovirus (Ad) vector encoding multiple highly networked epitopes and assess its ability to induce CTL responses in vivo. Effective CTL- mediated responses to highly networked epitopes identified by structure-based network analysis may limit viral rebound from latently infected CD4+ T cells and thereby may guide the rational design of a therapeutic CTL- based vaccine for HIV-1.

项目概要/摘要该提案提出了一个专注于 CTL 研究的五年研究职业发展计划对高度“网络化”表位的反应作为一组新的不变靶标，包含在治疗性 CTL 中该候选人目前是哈佛医学院的医学讲师，并且马萨诸塞州总医院胃肠病科提出的建议以候选人之前在 HIV-1 免疫学和生物化学方面的研究经验，他在其中定义了 CTL 带有结构和功能限制的表位，并且是个体优先靶向的表位他现在在他的导师 Bruce Walker 博士的指导下，自然控制了 HIV-1。 MGH、麻省理工学院和哈佛大学的 Ragon 研究所，以确定这些表位是否可能是有价值的 CTL 靶点拟议的实验和教学工作将为候选人定位。拥有一套独特的技能，使他能够过渡到作为一名医学科学家在该领域的独立地位预防性和治疗性 HIV-1 疫苗接种。艾滋病毒/艾滋病的流行继续在全世界范围内产生巨大的医疗、社会和经济影响。虽然联合抗逆转录病毒疗法 (cART) 有助于大大减轻全球艾滋病毒负担，但病毒建立持久潜伏病毒库的能力需要对艾滋病毒感染者进行终生治疗因此，可以抑制或消除病毒库从而限制艾滋病毒的新方法。最近的努力主要集中在细胞毒性 T 细胞的诱导上。作为治疗性疫苗的潜在靶点然而，CTL 的积累逃脱了突变。慢性感染 cART 抑制的患者限制了成功预防病毒反弹的能力在博士后研究期间，该候选人开发了一种称为 cART 的新方法。基于结构的网络分析，可识别由广泛的 HLA 等位基因呈现的特定表位，他还证明了高度“网络化”的 CTL 表位的靶向性。能够区分自发控制 HIV-1 的个体和患有进展性疾病的个体。候选人现在重新认识到 CTL 介导的免疫反应针对高度“网络化” 在接受 cART 治疗的慢性感染者中，表位还可以抑制 cART 停止后的病毒生长该假设将通过以下目标进行检验：1）对个体进行深度突变扫描。原病毒 DNA 中高度网络化的表位，2) 评估针对高度网络化表位的 CTL 是否可以抑制 cART 治疗患者的病毒生长，以及 3) 开发编码腺病毒 (Ad) 载体多个高度网络化的表位并评估其在体内诱导 CTL 反应的能力。对基于结构的网络分析确定的高度网络化表位的介导反应可能会限制病毒潜伏感染的 CD4+ T 细胞的反弹，从而可以指导治疗性 CTL- 的合理设计基于 HIV-1 的疫苗。