Defining the biological relevance of HIV specific HLA-E restricted CD8 T cell responses

定义 HIV 特异性 HLA-E 限制性 CD8 T 细胞反应的生物学相关性

• 批准号: 10393699
• 负责人: Anju Bansal
• 金额: $ 105.04万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-16 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10393699
• 关键词: Acute; Address; Alleles; Antibodies; Antigens; Binding; Biological; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Characteristics; Chronic; Data; Epitopes; Foundations; Frequencies; Future; GTP-Binding Proteins; Gene Expression; Gene Expression Profile; Genetic; Genetic Polymorphism; Goals; Grant; HIV; HIV Infections; HIV Seronegativity; HIV therapy; HIV vaccine; HIV-1; HLA G antigen; HLA-A gene; Immune; Immunologic Surveillance; Individual; Infection; Interferon Type II; KLRD1 gene; Knowledge; Macaca; Macaca mulatta; Mediating; Methodology; Modality; Molecular; Molecular Profiling; Natural Killer Cells; Outcome; Pathogenicity; Patients; Peptide Leader Sequences; Peptides; Phenotype; Prevention; Preventive vaccine; Process; Proteins; Proteome; Publishing; Reagent; Reporting; Resources; Role; SIV; Sampling; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Therapeutic; Time; Vaccinated; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Viral Physiology; Virus; Virus Diseases; Work; acute infection; adaptive immunity; alpha-beta T-Cell Receptor; base; chronic infection; efficacy study; experimental study; improved; in vitro activity; insight; novel; pathogen; peptide I; receptor; response; single-cell RNA sequencing; tool; vaccine efficacy; vector

PROJECT SUMMARY HLA-E restricted CD8 T cells specific to a diverse repertoire of viral and bacterial peptides have been reported indicating their role in adaptive immunity. Due to their limited polymorphism, peptide presentation through HLA- E can be considered advantageous for vaccine design. In SIV/macaque studies, protection from pathogenic SIV challenge was observed in 50% rhesus macaques vaccinated with an RhCMV based vector. This unprecedented protection was independent of antibodies and attributed in part to an induction of MHC-E restricted CD8 T cells. Despite promising findings from several viral infections, role of HLA-E specific CD8 T cells in HIV has been grossly understudied. In fact, no study to date has examined the role of HLA-E restricted CD8 T cells (E-CD8s) in HIV infection and vaccination. The only published data to suggest the presence of HLA-E restricted HIV- specific CD8 T cells are experiments demonstrating that HIV peptides can bind to HLA-E. Since HLA-Ia and E are ubiquitously co-expressed, a significant gap in our knowledge has largely been due to absence of biological reagents to delineate the contribution of HLA-Ia vs. HLA-E alleles in HIV. Our group has generated HLA-E specific reagents to address the missing gaps in information on the relevance of HLA-E restricted CD8 T cells targeting HIV. Our preliminary data shows that HLA-E restricted CD8 T cell responses specific for 2 epitopes in Gag can be detected in chronic HIV infection. In many cases, these responses were not only restricted by E allele but also by classical HLA-Ia alleles. Furthermore, in small subset of HIV infected individuals, we observed that in individuals who control virus, without any ART i.e. controllers mounted HLA-E restricted CD8 T cell responses that were polyfunctional and higher in magnitude. In comparison, viremic individuals on ART mounted lower magnitude of HLA-E restricted CD8 T cell responses that mainly induced IFN-γ and CD107 expression. We also show that Gag epitopes are presented by HLA-E in an HIV infected cell. Finally, our pilot data shows priming of HLA-E restricted CD8 T cell responses in HIV seronegative donors. The latter underscores the need to see if these responses are induced by preventative vaccines and if not how can these be optimized and harnessed for effective HIV vaccines. Our strong preliminary findings are foundational for the work proposed in the current grant. Our overarching goal is to address the central question of whether HIV is impacted by the frequency, breadth, and functionality of HLA-E restricted CD8 T cells. Based on our data, we hypothesize that dually restricted CD8 T cells will be associated with a broader response which would be useful for a preventative vaccine and make HIV escape more difficult. Aim 1, determines the relevance of HLA-E restricted CD8 T cells in HIV infection and vaccination. We will use samples from acute/chronic infection and 2 prior CTL based HIV vaccines. Aim 2 uses single cell based analyses to determine αβTCR repertoire and gene expression patterns of HIV specific CD8 T cells restricted by HLA-E and how these molecular signatures relate to viral control.

项目摘要 据报道，HLA-E受到限制的CD8 T细胞，据报道了病毒和细菌的潜水库。 表明它们在适应性免疫中的作用。由于它们的多态性有限，肽的表现通过HLA- E可以被认为是疫苗设计有利的。在SIV/猕猴研究中，防止致病性SIV保护 在用基于RHCMV的载体接种疫苗的50％恒河猕猴中观察到了挑战。这个空前的 保护与抗体​​无关，部分归因于诱导MHC-E受限的CD8 T细胞。 尽管从几种病毒感染中发现了有希望的发现，但HLA-E特异性CD8 T细胞在HIV中的作用一直是 非常理解。实际上，迄今为止尚未研究HLA-E受限的CD8 T细胞（E-CD8S）的作用 在HIV感染和疫苗接种中。唯一提示存在HLA-E受限的HIV-的数据 特定的CD8 T细胞正在实验，HIV肽可以与HLA-E结合。由于HLA-IA和E 无处不在地表达，我们所知的显着差距很大程度上是由于没有生物学 描述HLA-IA与HLA-E等位基因艾滋病毒的贡献的试剂。我们的小组已经产生了HLA-E 特定试剂以解决有关HLA-E限制CD8 T细胞相关性信息中缺失的差距 针对艾滋病毒。我们的初步数据表明，HLA-E限制了针对2个表位的CD8 T细胞反应 在慢性HIV感染中可以检测到插科打g。在许多情况下，这些反应不仅受E的限制 等位基因，但还通过古典HLA-IA等位基因。此外，在艾滋病毒感染的个体的一小部分中，我们观察到 在控制病毒的个体中，没有任何艺术 多功能且幅度较高的响应。相比之下，ART上的病毒性个体 HLA-E限制的CD8 T细胞反应的较低幅度主要诱导IFN-γ和CD107表达。 我们还表明，HLA-E在HIV感染的细胞中提出了GAG表位。最后，我们的飞行员数据显示 HLA-E限制的CD8 T细胞反应的启动在HIV血清剂供体中。后者强调了需求 查看这些反应是否是由预防疫苗诱导的，如果没有，则如何优化这些反应 利用有效的HIV疫苗。我们强大的初步发现是针对提出的工作的基础 当前的赠款。我们的总体目标是解决艾滋病毒是否受到影响的核心问题 HLA-E受限的CD8 T细胞的频率，广度和功能。根据我们的数据，我们假设 双重限制的CD8 T细胞将与更广泛的响应有关，这对于预防性很有用 疫苗并使艾滋病毒逃脱更加困难。 AIM 1，确定HLA-E受限的CD8 T细胞的相关性 在HIV感染和疫苗接种中。我们将使用来自急性/慢性感染的样品和2个先前基于CTL的HIV 疫苗。 AIM 2使用基于单细胞的分析来确定αβTCR库和基因表达模式 受HLA-E限制的HIV特异性CD8 T细胞以及这些分子特征如何与病毒控制有关。