Exploiting Highly Networked CTL Epitopes to Achieve a Functional HIV Cure

利用高度网络化的 CTL 表位实现功能性 HIV 治愈

• 批准号: 10475751
• 负责人: Gaurav Das Gaiha
• 金额: $ 49.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475751
• 关键词: AIDS/HIV problem; Adoptive Transfer; Algorithms; Alleles; Anatomy; Area; Blood; CD4 Positive T Lymphocytes; Cell Separation; Cells; Chronic; Clone Cells; Coculture Techniques; Collaborations; Core Facility; Cytolysis; Cytotoxic T-Lymphocytes; DNA; Data; Drug resistance; Drug toxicity; Effectiveness; Epidemic; Epitopes; Fellowship; Goals; HIV; HIV vaccine; Impairment; Individual; Investigation; Knowledge; Life; Link; Mediating; Medical; Methodology; Mission; Modality; Mutagenesis; Mutate; Mutation; Network-based; Pathway Analysis; Patients; Pharmaceutical Preparations; Postdoctoral Fellow; Progressive Disease; Proteome; Public Health; Publishing; Research; Resources; Rest; Science; Site; Structure; T cell response; T-Lymphocyte Epitopes; Therapeutic; Tissue Sample; Tissues; United States National Institutes of Health; Vaccine Design; Vaccines; Viral; Viral reservoir; Virus; Virus Latency; Virus Replication; Work; antiretroviral therapy; base; deep sequencing; design; economic implication; gastrointestinal; humanized mouse; in vivo; innovation; latent HIV reservoir; mouse model; novel; novel strategies; novel therapeutics; peripheral blood; prevent; protein structure; rational design; resistance mutation; response; theories; therapeutic vaccine; therapeutically effective; viral rebound

ABSTRACT The HIV/AIDS epidemic continues to have enormous medical, societal and economic implications worldwide. While combination anti-retroviral therapy (cART) has greatly reduced the global burden of HIV, the ability of the virus to establish a persistent reservoir within the body requires that HIV-infected individuals remain on lifelong treatment. As a result, new modalities that can suppress the viral reservoir and thereby limit the requirement of HIV treatment are greatly needed. Recent efforts have been focused on the induction of cytotoxic T cells (CTLs) by therapeutic vaccines. However, the accumulation of CTL escape mutations in chronically infected, cART-suppressed patients has greatly limited the ability of CTLs to successfully prevent viral rebound following cART cessation. Thus, in order to counteract this viral escape, this DP2 proposal will focus on the study of CTL responses to a new set of targets, known as `highly networked' epitopes, to determine whether they can form the basis of a novel therapeutic CTL-based vaccine for HIV. These highly networked epitopes were identified using an innovative approach known as structure-based network analysis. By applying network theory principles to HIV protein structure data, the approach was able to identify a set of epitopes that are intolerant to mutation, but which are also presented by a broad array of HLA alleles. Moreover, the targeting of highly networked epitopes by functional CTL responses was shown to strongly distinguish individuals who naturally control HIV from those with progressive disease. Thus, the goal now is to determine whether CTLs directed against highly networked epitopes can also suppress viral outgrowth following cART cessation in the remaining ~99% of chronically-infected, cART-treated individuals. This will be accomplished by: (i) deep sequencing highly networked epitopes in proviral DNA derived from peripheral blood and gastrointestinal tissue and (ii) determining whether CTLs targeting highly networked epitopes can suppress latent virus outgrowth both ex vivo and in a humanized mouse model. Demonstrating the effectiveness of CTL-mediated responses to highly networked epitopes will confirm the value of the structure-based network analysis approach to guide the rational design of a effective, therapeutic CTL-based vaccine for HIV.

摘要 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）大大减少了艾滋病毒的全球负担， 病毒在体内建立一个持久的水库需要艾滋病毒感染者保持终身 治疗因此，可以抑制病毒储库并由此限制对免疫调节剂的需求的新的模式被提出。 艾滋病毒治疗非常必要。最近的努力集中在诱导细胞毒性T细胞 （CTL）的治疗性疫苗。然而，在慢性感染， cART抑制的患者极大地限制了CTL成功预防病毒反弹的能力， cART停止。因此，为了对抗这种病毒逃逸，本DP 2提案将集中于CTL的研究 对一组新靶点的反应，称为“高度网络化”表位，以确定它们是否可以形成 一种新的治疗性CTL疫苗的基础。这些高度网络化的表位被鉴定为 使用一种创新的方法，称为基于结构的网络分析。应用网络理论 根据HIV蛋白质结构数据的基本原理，该方法能够识别出一组对HIV不耐受的表位。 突变，但也提出了广泛的HLA等位基因。此外，针对高度 通过功能性CTL应答的网络化表位显示出强烈区分自然 控制艾滋病毒从那些进行性疾病。因此，现在的目标是确定CTL是否定向 针对高度网络化的表位也可以抑制在剩余的cART停止后的病毒生长。 约99%的慢性感染者接受cART治疗。这将通过以下方式实现：（i）深度测序 来源于外周血和胃肠道组织的前病毒DNA中的高度网络化表位，和（ii） 确定靶向高度网络化表位的CTL是否可以抑制潜伏病毒的生长， 体内和人源化小鼠模型中。证明CTL介导的对高度免疫应答的有效性。 网络表位将证实基于结构的网络分析方法的价值，以指导 合理设计有效的、治疗性的基于CTL的HIV疫苗。