Impact of cross-reactive CD8 T cells on HIV-1 viral control and evolution

项目总结 此NIH F30应用程序的目的是为PI Sushma Boppana获得支持，以进行有指导的研究 以及在她的医学/博士学位培训中的职业发展活动，这将增强她成为 一位成功的内科科学家。该项目的目标是发展免疫学技能，使PI能够研究 用尖端实验室分析和计算技术研究急性HIV-1感染中CD8的交叉反应。 该研究提案的主要目标是调查交叉反应性CD8反应对 急性HIV-1感染对病毒控制和进化的影响。CD8 T细胞在HIV-1病毒控制中的关键作用 感染，很可能是未来有效治疗方法的一个重要组成部分。然而，病毒的潜伏期 蓄水池是实现HIV-1功能性或完全治愈的主要障碍。这个水库现在是 已知编码大量逃逸突变，CD8T细胞有可能在治疗上 为了清除感染者体内的HIV-1，需要识别同一病毒的多个变种 表位；换句话说，它们需要具有交叉反应。这个项目试图量化CD8的数量 急性感染中的交叉反应，以表征这些反应的功能，并建立 这些交叉反应对病毒控制的影响(目标1)。这项提案还将决定 单个TCR克隆型对目标1和目标1中CD8反应的总体交叉反应的贡献 将阐明CD8交叉反应对病毒进化的影响，将交叉反应反应与 病毒多样性减少(目标2)。我们研究的长期目标是更好地理解 HIV-1中CD8 T细胞的交叉反应，使未来的治疗策略可以更有效地操纵CD8 清除变异编码潜在储集层的反应。 建议的PI培训计划是由她的博士导师Paul Goepfert博士赞助的。包括在培训中 计划是将帮助PI在三个主要领域发展的经验：1)严格的免疫学研究 HIV-1，包括熟悉现有文献，批判性地评估已发表的研究，以及 关于科学诚信、负责任的研究以及严谨和可重复性原则的培训；2) 在生物信息技术和生物统计分析方面的能力；以及3)职业和职业发展， 包括基金撰写，期刊文章评审，通过演示文稿和稿件进行清晰的沟通 准备，并将研究成果转化为临床应用。这项培训计划的总体目标是 为PI作为一名内科科学家的成功职业生涯奠定坚实的基础，并拥有终极职业生涯 目标是领导一个合作研究团队，弥合以实验室为基础的人类免疫学之间的差距 传染病的研究和临床防治。

PROJECT SUMMARY The purpose of this NIH F30 application is to obtain support for the PI, Sushma Boppana, for mentored research and career development activities within her MD/PhD degree training that will strengthen her potential to become a successful physician scientist. The project goal is to develop skills in immunology that will allow the PI to study CD8 cross-reactivity in acute HIV-1 infection using cutting edge laboratory assays and computational techniques. The primary objective of the research proposal is to investigate the impact of cross-reactive CD8 responses in acute HIV-1 infection on viral control and evolution. CD8 T cells play a critical role in viral control during HIV-1 infection and are likely to be an important component of future effective cure therapies. However, the viral latent reservoir represents a major obstacle to achieving functional or complete cure in HIV-1. This reservoir is now known to encode significant numbers of escape mutations, and it is possible that CD8 T cells therapeutically directed towards clearing HIV-1 in infected individuals will need to recognize multiple variants of the same epitopes; in other words, they will need to be cross-reactive. This project seeks to quantify the amount of CD8 cross-reactivity seen in acute infection, to characterize the functionality of these responses, and to establish the impact of these cross-reactive responses on viral control (Aim 1). This proposal will also determine the contribution of individual TCR clonotypes to the overall cross-reactivity of the CD8 responses seen in Aim 1 and will elucidate the impact of CD8 cross-reactivity on viral evolution by correlating cross-reactive responses to diminished viral diversity (Aim 2). The long-term objective of our research is to better understand the role of cross-reactive CD8 T cells in HIV-1 such that future cure strategies can more effectively manipulate the CD8 response to clear a variant-encoding latent reservoir. The proposed training plan for the PI is sponsored by her PhD mentor, Dr. Paul Goepfert. Included in the training plan are experiences that will help the PI develop in three major areas: 1) rigorous immunological research in HIV-1, including developing familiarity with the existing literature, critically evaluating published studies, and training in principles of scientific integrity, responsible conduct of research, and rigor and reproducibility; 2) competence in bioinformatic techniques and biostatistical analysis; and 3) career and professional development, including grant writing, journal article review, clear communication through presentation and manuscript preparation, and translation of research findings to clinical application. The overall goal of this training plan is to provide the PI with a solid foundation for a successful career as a physician scientist, with the ultimate career goal of leading a collaborative research team that bridges the gap between laboratory-based human immunology research and the clinical prevention and treatment of infectious diseases.