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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的艾滋病毒/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) 极大地减轻了全球艾滋病毒负担，但病毒在体内建立持久储存库需要艾滋病毒感染者终生保持治疗。因此，可以抑制病毒储存库并从而限制对病毒的需求的新方法非常需要艾滋病毒治疗。最近的努力集中在细胞毒性 T 细胞的诱导上（CTL）通过治疗性疫苗。然而，慢性感染者中 CTL 逃逸突变的积累， 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，为了抵消这种病毒逃逸，该DP2提案将重点关注CTL的研究对一组新目标（称为“高度网络化”表位）的反应，以确定它们是否可以形成一种基于 CTL 的新型 HIV 治疗疫苗的基础。鉴定了这些高度网络化的表位使用称为基于结构的网络分析的创新方法。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耐受的表位突变，但也由广泛的 HLA 等位基因呈现。此外，目标高度通过功能性 CTL 反应形成的网络化表位可以强烈地区分自然的个体控制患有进行性疾病的人的艾滋病毒。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 cART 停止后的病毒生长约 99% 的慢性感染者接受过 cART 治疗。这将通过以下方式实现： (i) 深度测序源自外周血和胃肠道组织的原病毒 DNA 中高度网络化的表位，以及 (ii) 确定针对高度网络化表位的 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 介导的对高度反应的有效性网络化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。