Viral adaptation to CD4 T cell responses and the impact on HIV immunity

摘要 强大的CD 4 T细胞反应可能是任何保护性艾滋病毒疫苗的关键，通过其多方面的作用。 支持免疫效应，但作为HIV感染的主要目标，它们对宿主免疫的贡献 相对来说，被低估了。我们最近证明了CD 4 T细胞免疫应答能够 驱动病毒适应，但这种活动的机制及其与整体疾病发病机制的相关性是 未知CD 4 T细胞亚群，T滤泡辅助细胞（Tfh），已成为研究的焦点， 其作用 在B细胞分化和成熟以及其促进病原体特异性高亲和力中和 抗体反应。 CD 4 T细胞也具有细胞毒性潜力，我们已经证明， 病毒表位的单个氨基酸变化表明在病毒逃逸中的作用。我们假设病毒 适应性损害了CD 4 T细胞的免疫功能，导致了 艾滋病毒和影响疾病的临床过程。我们将在三个独立的目标中测试这一假设： 具体目标1：通过TCR测序，确定病毒适应对CD 4 T细胞的影响 结合抗原并响应刺激而适当激活的能力。 具体目的2：定义病毒适应对CD 4 T细胞效应子功能的影响，如以下表达： 细胞毒性能力和Tfh表型的扩增。 具体目标3：确定感染高度适应病毒的人是否加速HIV-1 临床疾病进展。 提出的目标将揭示病毒适应CD 4 T细胞免疫压力的机制， 对疾病的影响。为了支持这些努力，我制定了一个合作计划， 获得来自已故捐赠者的初级组织，提供了一个独特的机会来证实发现 在外周血样品中观察到的与来自组织来源的淋巴细胞的那些。导师团队 结合了培训生发展的良好记录和与计划最相关领域的专业知识， 实验我还提供了一门旨在增强我的免疫学知识、技术 曲目、统计知识和专业发展。这项建议将有助发展 确定临床相关研究问题和促进免疫理解所需的技能， 艾滋病毒和其他慢性病毒感染。

ABSTRACT Robust CD4 T cell responses are likely to be critical for any protective HIV vaccine through their multifaceted support of immune effectors, but as the primary targets of HIV infection their contribution to host immunity has been relatively understudied. We have recently demonstrated CD4 T cell immune responses are capable of driving viral adaptation, but the mechanism of this activity and its relevance to overall disease pathogenesis is unknown. A CD4 T cell subset, the T follicular helper cell (Tfh), has become a focus of investigation for its role in B cell differentiation and maturation as well as its facilitation of pathogen-specific high-affinity neutralizing antibody responses. CD4 T cells also have cytotoxic potential, a phenotype we have shown is compromised by single amino acid changes in viral epitopes suggesting a role in viral escape. We hypothesize viral adaptation compromises the immunologic functions of CD4 T cells resulting in a survival benefit for HIV and impacting the clinical course of disease. We will test this hypothesis in three separate aims: Specific Aim 1: Through TCR sequencing, determine the effects of viral adaptation on CD4 T cells ability to bind antigen and appropriately activate in response to stimulation. Specific Aim 2: Define the impact of viral adaptation on CD4 T cell effector functions as expressed by cytotoxic capacity and expansion of the Tfh phenotype. Specific Aim 3: Determine whether persons infected with highly adapted virus have accelerated HIV-1 clinical disease progression. The proposed aims will reveal the mechanism underlying viral adaptation to CD4 T cell immune pressure and the impact on disease. To support these efforts, I have developed a collaborative program that will provide access to primary tissues from deceased-donors, offering a unique opportunity to corroborate findings observed in peripheral blood samples with those from tissue-derived lymphocytes. The mentorship team combines a strong record of trainee development and expertise in the areas most relevant to the planned experiments. I also present a curriculum designed to enhance my immunologic knowledge, technical repertoire, statistical knowledge and professional development. The proposal will facilitate development of the skills necessary to identify clinically relevant research questions and advance the understanding of immunity to HIV and other chronic viral infections.