Defining the biological relevance of HIV-1 adaptation to CD4 T cell responses

定义 HIV-1 适应与 CD4 T 细胞反应的生物学相关性

• 批准号: 10186453
• 负责人: Paul A. Goepfert
• 金额: $ 62.81万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186453
• 关键词: Acute; Address; Affect; Alleles; Amino Acid Substitution; Amino Acids; Antiviral Agents; Biological; Biological Assay; CD4 Positive T Lymphocytes; Cell physiology; Cells; Clinical; Clinical Course of Disease; Clinical Markers; Computer Analysis; Cytometry; Disease; Disease Progression; Epitopes; Evolution; Frequencies; Future; Genetic; Goals; HIV; HIV Infections; HIV vaccine; HIV-1; HIV-1 vaccine; Immune; Immune response; Immunity; Immunologic Surveillance; Impairment; Individual; Infection; Link; Maps; Measures; Mediating; Mutation; Outcome; Pathogenesis; Patients; Peruvian; Phenotype; Population; Prevention; Preventive vaccine; Regimen; Role; T cell response; T-Lymphocyte Epitopes; Techniques; Testing; Vaccine Design; Vaccines; Variant; Viral; Viral Load result; Virus; acute infection; adaptive immunity; antiretroviral therapy; base; cohort; design; efficacy study; immune activation; immunogenic; immunogenicity; in vivo; novel; preservation; pressure; response; transcriptomics; treatment optimization

Project Summary Due to their multiple roles in adaptive immunity, induction of robust CD4 T cells (CD4) is a desirable goal for any preventative vaccine. Since these cells are the primary targets of HIV infection, their antiviral role in HIV immunity has been relatively understudied. We have shown immune pressure by effector CD4 drive viral escape, but the role of these cells and the implications of CD4 immune escape in HIV pathogenesis is unclear. We linked amino acid changes (termed mutations or adaptations) to specific HLA-II alleles and defined adapted epitopes (AE), where single amino acid substitutions reflect CD4-mediated immune pressure. The complementary non- adapted epitope (NAE) shows no evidence of mutation when assessed at a population level. These adaptations can accrue in a viral population, and the extent of adaptation in a new host is dependent upon their respective HLA-II alleles. We previously confirmed that AE represent immune escape from CD4 T cells and found the magnitude and function of AE-specific CD4 T cell responses were diminished, but the impact of CD4-restricted epitope adaptations on CD4 T cell immunity is unknown. Our overall hypothesis is that CD4 T cells targeting- NAE have a distinct functional phenotype able to control HIV replication, which is compromised by viral adaptation to these responses. Since initiating ART immediately after infection preserves CD4 T cells, this application will address whether early ART promotes better viral control by allowing CD4 T cells to target NAE, responses known to be beneficial as compared to AE. We will test this hypothesis using a unique cohort of clade B acutely infected Peruvians where patients receive antiretroviral therapy (ART) either immediately or 6 months post infection. In specific aim 1, we will determine the biologic relevance of HIV adaptation to CD4 T cells. To do so, we will determine the ability of CD4 T cells to inhibit virus that is fully adapted or non-adapted to these responses. We will also assess the extent to which HLA-II adaptation in the transmitted virus influences clinical disease course in that individual. In specific aim 2, we will decipher the functional differences (globally and at single cell level) that define an AE or NAE specific CD4 T cell response and determine whether immediate ART optimizes CD4 T cells by targeting NAE encoded in the infecting virus. In specific aim 3, we will determine the impact of CD4 T cell adaptation on vaccine immunogenicity and efficacy. We will evaluate the function of CD4 T cells in vaccinees as it relates to NAE and AE responses. We will also determine whether adaptation of the vaccine insert influences rates of HIV infection. In summary, CD4 T cell mediated escape implies an in-vivo survival advantage of HIV adaptation and suggests CD4 T cells are indeed important to immune control of HIV. Elucidating the mechanisms of CD4 T cell immunity in HIV infection and the relevance of HIV escape to these responses will benefit the design of future HIV-1 preventative vaccine strategies.

项目摘要 由于它们在自适应免疫中的多重作用，诱导CD4 T细胞的诱导是任何对任何目标的理想目标 预防性疫苗。由于这些细胞是HIV感染的主要靶标，因此它们在HIV免疫中的作用 已经相对局限了。我们已经通过效应子CD4驱动病毒逃生显示了免疫压力，但是 这些细胞的作用以及CD4免疫逃逸在HIV发病机理中的影响尚不清楚。我们连接了氨基 酸变化（称为突变或适应）对特定的HLA-II等位基因和定义的适应性表位（AE）， 单个氨基酸取代反映CD4介导的免疫压力。互补的非 在人群水平评估时，改编的表位（NAE）没有显示突变的迹象。这些改编 可以在病毒人群中累积，而新宿主的适应程度取决于它们各自的 HLA-II等位基因。我们先前证实AE代表从CD4 T细胞中免疫逃生，发现 AE特异性CD4 T细胞反应的大小和功能减少了，但CD4限制的影响 CD4 T细胞免疫的表位适应尚不清楚。我们的总体假设是CD4 T细胞靶向 NAE具有独特的功能表型，能够控制HIV复制，该表型被病毒损害 适应这些反应。 由于感染后立即启动ART可以保留CD4 T细胞，因此该应用将解决早期的 艺术通过允许CD4 T细胞靶向NAE来促进更好的病毒控制，该反应被称为有益 与AE相比。我们将使用独特的进化枝b急性感染的秘鲁人来检验这一假设 患者立即或感染后6个月接受抗逆转录病毒疗法（ART）。在特定目标1中，我们 将确定HIV适应CD4 T细胞的生物学相关性。为此，我们将确定 CD4 T细胞可抑制完全适应或不适应这些反应的病毒。我们还将评估 HLA-II在传播病毒中适应的程度影响该个体的临床疾病过程。在 特定的目标2，我们将破译定义AE或 NAE特异性CD4 T细胞响应并确定立即技术是否通过靶向CD4 T细胞优化CD4 T细胞 NAE编码在感染病毒中。在特定的目标3中，我们将确定CD4 T细胞适应对 疫苗免疫原性和功效。我们将评估疫苗中CD4 T细胞的功能，因为 NAE和AE响应。我们还将确定疫苗插入物的适应是否会影响艾滋病毒的发生率 感染。总而言之，CD4 T细胞介导的逃逸意味着HIV适应的体内生存优势和 表明CD4 T细胞确实对HIV的免疫控制确实很重要。阐明CD4 T细胞的机制 艾滋病毒感染的免疫力以及艾滋病毒逃生与这些反应的相关性将使未来的设计受益 HIV-1预防疫苗策略。