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/艾滋病流行在全球范围内仍然具有巨大的医学，社会和经济影响。虽然抗逆转录病毒疗法（CART）大大减轻了全球艾滋病毒负担，但在体内建立持续的水库的病毒需要艾滋病毒感染的人留在终生上治疗。结果，可以抑制病毒库的新方式，从而限制了非常需要艾滋病毒治疗。最近的努力集中在诱导细胞毒性T细胞上（CTL）通过治疗疫苗。但是，CTL逃脱突变在长期感染中的积累，被塞车的患者极大地限制了CTL成功防止病毒反弹的能力推车戒烟。因此，为了抵消这种病毒逃生，该DP2提案将集中于CTL的研究对一组新目标的响应，称为“高度网络”表位，以确定它们是否可以形成基于CTL的新型艾滋病毒疫苗的基础。确定了这些高度网络的表位使用称为基于结构网络分析的创新方法。通过应用网络理论 HIV蛋白结构数据的原理，该方法能够识别一组不宽容的表位突变，但也由各种HLA等位基因呈现。此外，高度定位通过功能CTL响应的网络表位显示出强烈区分自然的人从患有进行性疾病的患者控制艾滋病毒。因此，现在的目标是确定CTL是否指向在剩余〜99％的慢性感染，手推车处理的个体。这将通过：（i）深入测序源自周围血液和胃肠道组织的前病毒DNA的高度网络表位，（ii）确定针对高度网络表位的CTL是否可以抑制潜在病毒的生长体内和人源化的小鼠模型。证明CTL介导的对高度响应的有效性网络表位将确认基于结构的网络分析方法的价值，以指导有效的，基于CTL的艾滋病毒疫苗的合理设计。