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: 10246309
• 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/10246309
• 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; 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)极大地减轻了全球艾滋病毒的负担，但 病毒要在体内建立持久的蓄水池，需要艾滋病毒感染者终身存在 治疗。因此，可以抑制病毒库从而限制对 艾滋病毒的治疗是非常需要的。最近的努力主要集中在诱导细胞毒性T细胞上 (CTL)通过治疗性疫苗。然而，在慢性感染中，CTL逃逸突变的积累， CART抑制的患者极大地限制了CTL成功防止病毒反弹的能力 手推车停下来。因此，为了对抗这种病毒逃逸，DP2建议将重点放在CTL的研究上 对一组新的靶标的反应，称为高度网络化的表位，以确定它们是否可以形成 基于CTL的新型治疗性HIV疫苗的基础。这些高度网络化的表位被鉴定出来 使用一种称为基于结构的网络分析的创新方法。通过应用网络理论 根据HIV蛋白质结构数据的原理，该方法能够识别出一组不能耐受的表位 突变，但这也是由广泛的HLA等位基因表现出来的。此外，高度集中的目标 通过功能性CTL反应的网络表位被证明能够强烈地区分自然 从进展性疾病中控制艾滋病毒。因此，现在的目标是确定CTL是否指向 抗高度网络化的表位也可以抑制病毒在剩余的CART停止后的生长 约99%的慢性感染、接受购物车治疗的人。这将通过以下方式实现：(I)深度测序 来自外周血和胃肠道组织的前病毒DNA中高度联网的表位和(Ii) 确定针对高度网络化表位的CTL是否可以抑制潜伏的病毒增殖 在活体和人性化的老鼠模型中。证明CTL介导的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 合理设计一种有效的、基于CTL的治疗性HIV疫苗。