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

交叉反应 CD8 T 细胞对 HIV-1 病毒控制和进化的影响

• 批准号: 10231119
• 负责人: Sushma Boppana
• 金额: $ 4.73万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-03-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231119
• 关键词: Acute; Affect; Alleles; Area; Avidity; Bioinformatics; Biological Assay; Biometry; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clinical; Communication; Competence; Computational Technique; Data; Data Set; Development; Doctor of Philosophy; Enrollment; Epitopes; Evolution; Familiarity; Foundations; Future; Goals; Grant; HIV; HIV-1; Human; Immunologics; Immunology; Impairment; In Vitro; Individual; Infection; Interferon Type II; Knowledge; Laboratories; Left; Literature; Manuscripts; Measures; Mentors; Molecular; Mutation; Nature; Physicians; Play; Preparation; Prevention; Publishing; Reproducibility; Research; Research Proposals; Role; Scientist; Shapes; Solid; Surface; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Techniques; Therapeutic; Thymus Gland; Training; Translational Research; United States National Institutes of Health; Variant; Viral; Viral Load result; Virus; Virus Latency; Work; Writing; acute infection; antiretroviral therapy; base; career; career development; chronic infection; clinical application; cohort; computer studies; cross reactivity; curative treatments; cytotoxicity; experience; improved; infectious disease treatment; journal article; next generation sequencing; novel; research and development; response; responsible research conduct; screening; skills

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.

项目摘要 此NIH F30申请的目的是为PI Sushma Boppana获得指导研究的支持 和职业发展活动在她的MD/博士学位培训，将加强她的潜力，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能够学习 使用尖端实验室检测和计算技术研究急性HIV-1感染中的CD 8交叉反应性。 该研究提案的主要目标是调查交叉反应性CD 8应答对 急性HIV-1感染对病毒控制和进化的影响。CD 8 T细胞在HIV-1期间的病毒控制中发挥关键作用 并可能成为未来有效治愈疗法重要组成部分。然而，病毒潜伏 储库是实现HIV-1功能性或完全治愈的主要障碍。这个水库现在 已知编码大量的逃逸突变，并且CD 8 T细胞治疗上可能 为了清除感染者体内的HIV-1，需要识别同一病毒的多种变体。 表位;换句话说，它们需要交叉反应。该项目旨在量化CD 8的数量， 急性感染中观察到的交叉反应性，以表征这些反应的功能，并建立 这些交叉反应性应答对病毒控制的影响（目的1）。该提案还将确定 单个TCR克隆型对Aim 1中所见的CD 8应答的总体交叉反应性的贡献， 将阐明CD 8交叉反应性对病毒进化的影响， 减少病毒多样性（目标2）。我们研究的长期目标是更好地了解 HIV-1中的交叉反应性CD 8 T细胞，以便未来的治疗策略可以更有效地操纵CD 8 T细胞。 响应以清除变体编码潜在储库。 PI的拟议培训计划由其博士导师Paul Goepfert博士赞助。列入培训 计划的经验，将有助于PI在三个主要领域的发展：1）严格的免疫学研究， HIV-1，包括熟悉现有文献，批判性评价已发表的研究， 在科学诚信、负责任的研究行为以及严谨性和可重复性原则方面的培训; 2） 生物信息学技术和生物统计分析能力; 3）职业和专业发展， 包括资助写作、期刊文章评审、通过演讲和手稿进行清晰的沟通 准备，并将研究结果转化为临床应用。本培训计划的总体目标是 为PI提供作为医生科学家的成功职业生涯奠定坚实的基础， 目标是领导一个合作研究小组，弥合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。