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: 10254731
• 负责人: Anju Bansal
• 金额: $ 65.66万
• 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/10254731
• 关键词: Acute; Address; Alleles; Antibodies; Antigens; Antiviral Agents; 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 已经报道了HLA-E限制性CD 8 T细胞特异于多种病毒和细菌肽 表明它们在适应性免疫中的作用。由于它们有限的多态性，通过HLA-1的肽呈递是不可能的。 E可以被认为对疫苗设计有利。在SIV/猕猴研究中， 在用基于RhCMV的载体接种的50%恒河猴中观察到攻击。这一前所未有 保护作用不依赖于抗体，部分归因于MHC-E限制性CD 8 T细胞的诱导。 尽管从几种病毒感染中得到了有希望的发现，但HLA-E特异性CD 8 T细胞在HIV中的作用一直没有得到证实 被严重低估了事实上，迄今为止还没有研究检查HLA-E限制性CD 8 T细胞（E-CD 8 s）的作用。 艾滋病毒感染和疫苗接种。唯一发表的数据表明存在HLA-E限制性艾滋病毒- 特异性CD 8 T细胞是证明HIV肽可以结合HLA-E的实验。由于HLA-Ia和E 普遍存在共表达，我们知识中的一个重大空白主要是由于缺乏生物学上的 描述HLA-Ia与HLA-E等位基因在HIV中的作用的试剂。我们小组已经产生了HLA-E 用于填补HLA-E限制性CD 8 T细胞相关性信息缺失空白的特异性试剂 针对艾滋病毒。我们的初步数据表明，HLA-E限制性CD 8 T细胞应答特异于2个表位， Gag可以在慢性HIV感染中检测到。在许多情况下，这些反应不仅受到E 等位基因，但也由经典的HLA-Ia等位基因。此外，在一小部分HIV感染者中，我们观察到 在控制病毒的个体中，没有任何ART，即控制者安装了HLA-E限制性CD 8 T细胞， 多功能和更大规模的反应。相比之下，接受ART治疗的病毒血症个体数量增加 HLA-E限制的CD 8 T细胞应答的幅度较低，主要诱导IFN-γ和CD 107表达。 我们还表明，Gag表位是由HLA-E在HIV感染的细胞。最后，我们的试点数据显示， 在HIV血清阴性供体中引发HLA-E限制性CD 8 T细胞应答。后者强调需要 看看这些反应是否是由预防性疫苗诱导的，如果不是，如何优化这些反应， 用于有效的艾滋病疫苗。我们强有力的初步研究结果是在 目前的赠款。我们的首要目标是解决艾滋病毒是否受到艾滋病毒感染的影响这一核心问题。 HLA-E限制性CD 8 T细胞的频率、宽度和功能。根据我们的数据，我们假设 双重限制性CD 8 T细胞将与更广泛的反应相关，这将有助于预防性治疗。 疫苗，使艾滋病毒更难逃脱。目的1，确定HLA-E限制性CD 8 T细胞的相关性 艾滋病毒感染和疫苗接种。我们将使用来自急性/慢性感染和2例既往基于CTL的HIV的样本 疫苗。目的2：利用单细胞分析确定αβTCR库和基因表达模式 受HLA-E限制的HIV特异性CD 8 T细胞以及这些分子特征如何与病毒控制相关。