The impact of HIV adaptation to CD8 T cells on infection and viral control

HIV 对 CD8 T 细胞的适应对感染和病毒控制的影响

• 批准号: 10245517
• 负责人: Paul A. Goepfert
• 金额: $ 66.21万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245517
• 关键词: Acute; Adoptive Transfer; Alleles; Antigen-Presenting Cells; Area; Avidity; BLT mice; Biological; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chronic; Clinical; Cohort Analysis; Data; Dendritic Cells; Development; Disease Progression; Effectiveness; Epitopes; Flow Cytometry; Future; HIV; HIV Infections; HIV Seronegativity; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Human immunodeficiency virus test; Immune; Immune Targeting; Immune response; Immune system; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Kinetics; Light; Mediating; Messenger RNA; Mosaicism; Mutation; Outcome; Pathogenesis; Patients; Phase; Phenotype; Play; Prevention; Process; Role; Sampling; Sequence Analysis; Site; T cell response; Testing; Therapeutic; Vaccination; Vaccine Design; Vaccines; Viral; Viral Load result; Virus Diseases; Work; acute infection; alpha-beta T-Cell Receptor; antiretroviral therapy; base; chronic infection; cohort; cross reactivity; humanized mouse; immunogenic; in vivo; inflammatory milieu; mouse model; novel strategies; pressure; response; vaccine trial; viral fitness

PROJECT SUMMARY HIV-1 sequence diversity presents a formidable obstacle in the development of an efficacious preventative or therapeutic HIV-1 vaccine. Escape or adaptation from CD8 T cell mediated immune pressure is a major contributor to viral diversity. An adapted epitope (AE) encodes an HLA class I (HLA-I) associated escape mutation, while its counterpart non-adapted epitope (NAE) does not contain any evidence of HLA-I associated mutation or CTL escape. We previously showed that infection with a highly adapted HIV-1 strain was associated with a poor clinical outcome. The precise mechanism(s) responsible for this impaired viral control are not yet understood and is the focus of this study. Although AE are poorly immunogenic in acute HIV infection and following vaccination, our preliminary data show that CD8-AE are present during chronic HIV infection; however, these CD8-AE are generally low avidity responses in both acute and chronic infection. Longitudinal sequence analysis shows that these AEs do not undergo additional escape mutations or revert to the NAE form, despite immune pressure from CD8-AE. Our preliminary data also demonstrated that low avidity immune responses can induce a pro-inflammatory dendritic cell (DC) phenotype capable of trans-infecting CD4 T cells. Based on these findings, our premise holds that poorly functioning CD8-AE are conferring a viral fitness advantage. Our hypothesis is that CD8-AE contribute to HIV pathogenesis by failing to efficiently kill infected cells and thus creating an inflammatory environment that promotes HIV proliferation in a DC-dependent manner. To test this hypothesis, we will use samples obtained from humans (HIV infection and vaccination studies) and BLT-mice infected with HIV, thereby performing complementary in vitro and in vivo studies. In aim 1, we will determine the quality of CD8 T cell responses induced by NAE and AE. We will test the quality of CD8-NAE and AE-specific responses by analyzing a cohort of patients with acute infection followed for 6 months off antiretroviral therapy (ART) in addition to HIV seronegative individuals who received a mosaic vaccine encoding many AEs. In aim 2, we will determine whether AE-specific CD8 T cells induce a pro- inflammatory DC phenotype that enhances CD4 T cell trans-infection. We will characterize and compare the ability of CD8-NAE and AE specific cells to induce an inflammatory DC phenotype using samples obtained from acute infection and vaccination studies. Finally, aim 3 will determine whether infection with HIV encoding AEs exacerbates acute phase viral load kinetics and leads to an enhanced inflammatory state in an in-vivo humanized BLT mouse model. In summary, the role that HIV adaptation plays in the function of CD8 T cells is relatively understudied. Our proposal will help determine whether HIV specific CD8 T cells can be optimized to control viral infection and provide valuable information for future vaccine prevention and cure strategies. . .

项目摘要 HIV-1序列多样性在开发有效的预防或治疗HIV-1感染的药物中是一个巨大的障碍。 治疗性HIV-1疫苗逃避或适应CD 8 T细胞介导的免疫压力是一个主要的 病毒多样性的贡献者。适应性表位（AE）编码与HLA I类（HLA-I）相关的逃逸 突变，而其对应的非适应表位（NAE）不包含任何HLA-I相关的证据 突变或CTL逃逸。我们先前表明，感染高度适应的HIV-1毒株与 临床效果不佳。造成这种病毒控制受损的确切机制尚不清楚。 这是理解，也是本研究的重点。尽管AE在急性HIV感染中免疫原性差， 接种疫苗后，我们的初步数据显示慢性HIV感染期间存在CD 8-AE;然而， 这些CD 8-AE在急性和慢性感染中通常是低亲合力应答。纵向序列 分析表明，这些AE不会发生额外的逃逸突变或恢复为NAE形式， 来自CD 8-AE的免疫压力。我们的初步数据还表明，低亲合力免疫应答可以 诱导能够转感染CD 4 T细胞促炎树突细胞（DC）表型。基于这些 研究发现，我们的前提是，功能不良的CD 8-AE赋予病毒适应性优势。我们 假设是CD 8-AE通过不能有效地杀死感染细胞而促成HIV发病， 创造一个炎症环境，以DC依赖的方式促进HIV增殖。为了验证这一 假设，我们将使用从人类（HIV感染和疫苗接种研究）和BLT小鼠获得的样本 感染HIV，从而进行互补的体外和体内研究。在目标1中，我们将确定 NAE和AE诱导的CD 8 T细胞应答的质量。我们将检测CD 8-NAE和AE特异性 通过分析一组急性感染患者，然后停用抗逆转录病毒治疗6个月， (ART)除了接受编码许多AE的嵌合疫苗的HIV血清阴性个体之外。在目标2中， 我们将确定AE特异性CD 8 T细胞是否诱导促炎DC表型， T细胞反式感染。我们将表征和比较CD 8-NAE和AE特异性细胞诱导CD 8-NAE和AE特异性细胞的能力。 使用从急性感染和疫苗接种研究获得的样品的炎性DC表型。最后， 目的3将确定编码AE的HIV感染是否会加重急性期病毒载量动力学， 导致体内人源化BLT小鼠模型中炎症状态增强。总而言之， HIV适应在CD 8 T细胞功能中的作用相对研究不足。我们的建议将有助于确定 HIV特异性CD 8 T细胞是否可以优化以控制病毒感染，并提供有价值的信息， 未来的疫苗预防和治疗策略。 . .