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.

项目摘要/摘要 该建议提出了一项五年研究职业发展计划，重点是CTL的研究 对高度“网络”表位的反应是一组新的不变目标，其中包括在治疗性的CTL-中 HIV-1的疫苗目前是哈佛医学院的医学教练 马萨诸塞州总医院的胃术。 候选人以前在HIV-1免疫学和生物化学方面定义了CTL的研究经验 具有结构性和功能约束的表位，并且是个人最享有目标的表位 在他的导师布鲁斯·沃克（Bruce Walker）的指导下 MGH，麻省理工学院和哈佛大学Ragon研究所，以确定表位是否可以CTL目标 在接受治疗的个体中。 具有独特的技能，使他能够过渡到独立性 预防性和治疗性HIV-1疫苗学。 艾滋病毒/艾滋病的流行继续在全球拥有巨大的医疗，社会和经济影响。 虽然抗逆转录病毒疗法（CART）有助于大大减轻全球艾滋病毒负担，但 病毒建立持续迟到的能力需要终身治疗的艾滋病毒感染者 结果。 非常需要治疗持续时间。 作为治疗疫苗的潜在靶标。 长期感染的被抑制的手推车抑制的患者限制了发现成功预防病毒反弹的能力 候选人在博士博士后奖学金期间开发了一种新方法 基于结构的网络分析，标识了特定的表位，由一系列HLA Allels提出， 对突变的不宽容。 能够区分自发控制HIV-1与进行性疾病的个体 候选人现在假设CTL介导的免疫反应对高“网络”反应 表位还可以抑制慢性感染治疗的病毒式生长跟随马车购物车 个人。 在经过验证的DNA中高度网络的表位，2）评估针对高度网络表位的CTL是否可以 抑制手推车治疗的患者的病毒源生长，3）开发腺病毒（AD）载体编码 高度网络的表位和评估是在体内诱导CTL反应的能力。 通过基于结构的网络分析确定的对高度网络表位的介导反应可能会限制病毒 从潜在感染的CD4+ T细胞中反弹，从而可以指导治疗性CTL-的合理设计 基于HIV-1的疫苗。