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

• 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
• 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

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.

项目总结/摘要 该提案提出了一个为期五年的研究职业发展计划，重点是CTL的研究 对高度“网络化”表位的反应作为一组新的不变靶点，包括在治疗性CTL中， HIV-1疫苗。候选人目前是哈佛医学院的医学讲师， 马萨诸塞州总医院消化科。所概述的提案建立在 候选人以前在HIV-1免疫学和生物化学方面的研究经验，他定义了CTL 携带结构和功能限制的表位，以及个体优先靶向的表位 自然地控制HIV-1。他现在在他的导师布鲁斯步行者博士的指导下， Ragon Institute of MGH，MIT和哈佛的研究，以确定这些表位是否可以成为有价值的CTL靶点 治疗抑制的个体。拟议的实验和教学工作将定位候选人 他拥有一套独特的技能，使他能够在医学领域作为一名物理学家和科学家过渡到独立。 预防和治疗HIV-1疫苗学。 艾滋病毒/艾滋病流行病继续在全世界产生巨大的医疗、社会和经济影响。 虽然联合抗逆转录病毒疗法（cART）有助于大大减少艾滋病毒的全球负担， 病毒建立持久潜伏储库的能力需要对HIV感染者进行终身治疗 个体因此，可以抑制或消除病毒储存库从而限制HIV的新方法 治疗时间非常需要。最近的努力集中在诱导细胞毒性T细胞 作为治疗性疫苗的潜在靶点。然而，CTL逃逸突变的积累， 慢性感染的cART抑制患者限制了成功预防病毒反弹的能力， cART停止。在博士后研究期间，这位候选人开发了一种新方法， 基于结构的网络分析，其鉴定由广泛的HLA等位基因阵列呈递的特定表位， 它们不能耐受突变。他还证明了高度“网络化”的CTL表位的靶向作用， 能够区分自发控制HIV-1的个体和进行性疾病的个体。的 候选人现在假设CTL介导的免疫应答针对高度“网络化”的 表位也可以抑制慢性感染的cART治疗的cART停止后的病毒生长。 个体该假设将通过以下目的进行检验：1）对 2）评估靶向高度网络化表位的CTL是否可以 抑制来自cART治疗患者的病毒生长和3）开发腺病毒（Ad）载体，其编码 多个高度网络化的表位，并评估其在体内诱导CTL应答的能力。有效CTL- 通过基于结构的网络分析鉴定的对高度网络化表位的介导的应答可以限制病毒 从潜伏感染的CD 4 + T细胞反弹，从而可以指导治疗性CTL的合理设计。 HIV-1疫苗。