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

项目摘要 由于其在适应性免疫中的多重作用，诱导稳健的CD4 T细胞（CD4）是任何免疫疗法的理想目标。 预防性疫苗由于这些细胞是HIV感染的主要目标，它们在HIV免疫中的抗病毒作用 相对来说还没有得到充分的研究我们已经显示了效应CD4驱动病毒逃逸的免疫压力，但是 这些细胞的作用和CD4免疫逃逸在HIV发病机制中的意义尚不清楚。我们将氨基 特异性HLA-II等位基因的酸性变化（称为突变或适应）和确定的适应性表位（AE）， 其中单个氨基酸取代反映了CD4介导的免疫压力。补充非- 当在群体水平上评估时，适应表位（NAE）没有显示突变的证据。这些适应 可以在病毒群体中累积，并且在新宿主中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细胞的免疫逃逸，并发现AE与CD4 T细胞的免疫逃逸有关。 AE特异性CD4 T细胞应答的幅度和功能减弱，但CD4限制性T细胞应答的影响 CD4 T细胞免疫的表位适应是未知的。我们的总体假设是CD4 T细胞靶向- NAE具有能够控制HIV复制的独特功能表型，其受到病毒感染的影响。 适应这些反应。 由于在感染后立即启动ART可以保留CD4 T细胞，因此该应用将解决早期是否需要抗逆转录病毒治疗的问题。 ART通过允许CD4 T细胞靶向NAE来促进更好的病毒控制，已知这种反应对治疗NAE是有益的。 与AE相比。我们将使用一组独特的进化枝B急性感染的秘鲁人来检验这一假设， 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 将决定HIV适应CD4 T细胞的生物学相关性。为此，我们将确定 CD4 T细胞抑制完全适应或不适应这些反应的病毒。我们亦会评估 HLA-II在传播病毒中的适应性影响该个体的临床病程的程度。在 具体目标2，我们将破译定义AE或 NAE特异性CD4 T细胞应答，并确定立即ART是否通过靶向 感染病毒中编码的NAE。在具体的目标3中，我们将确定CD4 T细胞适应对 疫苗的免疫原性和有效性。我们将评估CD4 T细胞在疫苗接种者中的功能，因为它与以下因素有关： NAE和AE反应。我们还将确定疫苗插入物的适应性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适应的体内存活优势， 这表明CD4 T细胞确实对HIV的免疫控制很重要。阐明CD4 T细胞的作用机制 艾滋病毒感染的免疫力和艾滋病毒逃逸与这些反应的相关性将有利于未来的设计， HIV-1预防性疫苗策略。

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.