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

项目摘要 由于它们在获得性免疫中的多重作用，诱导强大的CD4T细胞(CD4T细胞)是任何 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 对此研究相对较少。我们已经证明了通过效应器CD4驱动病毒逃逸的免疫压力，但 这些细胞的作用以及CD4免疫逃逸在HIV发病机制中的意义尚不清楚。我们把氨基连接起来 特定的人类白细胞抗原-II等位基因的酸性变化(称为突变或适应)和定义的适应表位(AE)， 其中单一氨基酸的替换反映了CD4介导的免疫压力。互补性的非- 当在种群水平评估时，适应表位(NAE)没有显示突变的证据。这些改编 可以在病毒种群中积累，而在新宿主中的适应程度取决于它们各自的 人类白细胞抗原-II等位基因。我们之前证实了AE代表对CD4T细胞的免疫逃逸，并发现 AE特异性的CD4T细胞应答的幅度和功能减弱，但CD4T细胞的影响受限 CD4T细胞免疫的表位适应性尚不清楚。我们的总体假设是，CD4T细胞靶向- Nae具有独特的功能表型，能够控制艾滋病毒的复制，而艾滋病毒复制受到病毒的影响 适应这些反应。 由于感染后立即启动ART可以保存CD4T细胞，该应用程序将解决是否及早 ART通过允许CD4T细胞靶向NAE来促进更好的病毒控制，已知的反应有益于 与AE相比。我们将使用一组独特的B分支急性感染的秘鲁人来验证这一假设，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 将决定HIV适应与CD4T细胞的生物学相关性。要做到这一点，我们将确定 CD4T细胞抑制对这些反应完全适应或不适应的病毒。我们亦会评估 人类白细胞抗原II在传播病毒中的适应程度对该个体临床病程的影响程度。在……里面 具体目标2，我们将破译(全球和单个细胞水平)定义AE或 NAE特异性的CD4T细胞应答，并确定即刻ART是否通过靶向优化CD4T细胞 NAE编码在感染病毒中。在具体目标3中，我们将确定CD4T细胞适应对 疫苗的免疫原性和效力。我们将评估疫苗接种者的CD4T细胞的功能，因为它与 NAE和AE反应。我们还将确定疫苗插入的适应性是否会影响艾滋病毒的感染率 感染。总之，CD4T细胞介导的逃逸意味着艾滋病毒适应和体内生存的优势 提示CD4T细胞对HIV的免疫控制确实很重要。CD4T细胞作用机制的研究进展 艾滋病毒感染中的免疫和艾滋病毒逃逸与这些反应的相关性将有助于未来的设计 HIV-1预防性疫苗战略。

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.