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

基本信息

批准号：
9418347
负责人：
Paul A. Goepfert
金额：
$ 79万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9418347
关键词：
Acute Address Affect Alleles Amino Acid Substitution Amino Acids Antiviral Agents Biological Biological Assay Biological Preservation CD4 Positive T Lymphocytes Cell physiology Cells Clinical Clinical Course of Disease Clinical Markers Computer Analysis Cytometry Disease Disease Progression Epitopes Evolution Frequencies Future Goals HIV HIV Infections HIV vaccine HIV-1 HIV-1 vaccine Immune Immune response Immunity Immunologic Monitoring Impairment Individual Infection Link Maps Measures Mediating Mutation Outcome Pathogenesis Patients Peruvian Phenotype Population Prevention Preventive vaccine Regimen Role Techniques Testing Vaccine Design Vaccines Variant Viral Viral Load result Virus adaptive immunity antiretroviral therapy base cohort design efficacy study genetic profiling immune activation immunogenic immunogenicity in vivo novel pressure progression marker response transcriptomics

项目摘要

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.

项目概要由于其在适应性免疫中的多种作用，诱导强健的 CD4 T 细胞 (CD4) 是任何人的理想目标。预防性疫苗。由于这些细胞是 HIV 感染的主要目标，因此它们在 HIV 免疫中的抗病毒作用的研究相对较少。我们已经展示了效应子 CD4 驱动病毒逃逸的免疫压力，但是这些细胞的作用以及 CD4 免疫逃逸在 HIV 发病机制中的影响尚不清楚。我们连接氨基特定 HLA-II 等位基因和定义的适应表位 (AE) 的酸变化（称为突变或适应），其中单个氨基酸取代反映了 CD4 介导的免疫压力。互补的非在群体水平上进行评估时，适应表位（NAE）没有显示出突变的证据。这些改编可以在病毒群体中积累，新宿主的适应程度取决于它们各自的 HLA-II 等位基因。我们之前证实AE代表CD4 T细胞的免疫逃逸，并发现 AE 特异性 CD4 T 细胞反应的强度和功能减弱，但 CD4 限制性的影响 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，而这种复制会受到病毒的损害适应这些反应。由于感染后立即开始 ART 可以保留 CD4 T 细胞，因此该应用程序将解决是否早期 ART 通过允许 CD4 T 细胞靶向 NAE 来促进更好的病毒控制，已知这种反应是有益的与AE相比。我们将使用一组独特的 B 分支急性感染秘鲁人来检验这一假设，其中患者在感染后立即或 6 个月接受抗逆转录病毒治疗 (ART)。在具体目标 1 中，我们将确定 HIV 适应 CD4 T 细胞的生物学相关性。为此，我们将确定以下人员的能力： CD4 T 细胞能够抑制完全适应或不适应这些反应的病毒。我们还将评估传播病毒中 HLA-II 的适应性影响该个体临床病程的程度。在具体目标 2，我们将破译定义 AE 或单细胞水平的功能差异（全局和单细胞水平） NAE 特异性 CD4 T 细胞反应，并确定立即 ART 是否通过靶向优化 CD4 T 细胞 NAE 在感染病毒中编码。在具体目标 3 中，我们将确定 CD4 T 细胞适应对疫苗的免疫原性和功效。我们将评估疫苗接种者中 CD4 T 细胞的功能，因为它与 NAE 和 AE 反应。我们还将确定疫苗插入物的适应是否会影响艾滋病毒感染率感染。总之，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 细胞对于 HIV 的免疫控制确实很重要。阐明CD4 T细胞的机制 HIV 感染中的免疫力以及 HIV 逃逸与这些应对措施的相关性将有利于未来的设计 HIV-1 预防性疫苗策略。