Impact of HLA-II Adaptation on CD4 T-cell and Tfh responses in HIV-1 Vaccination

项目摘要 此NIH F30应用程序的目的是为PI Jacob Files获得对其指导研究的支持 未来三年的职业发展。这些活动是他的培训要求的一部分， 他必须获得他的MD/博士学位，他们将加强他的潜力，成为一个成功的 医学科学家该项目的主要目标是发展他的技能，以研究CD 4 + T细胞反应 (CD4使用免疫学实验室测定和计算机分析， 技术.该研究计划的主要目的是调查HLA-II相关病毒的影响， 在HIV-1疫苗接种背景下对CD 4应答的适应。研究发现，CD 4应答在 在产生HIV特异性抗体中起重要作用;因此，最佳的CD 4应答可能是 未来预防HIV-1疫苗的重要组成部分。我们的初步研究表明，目前的HIV-1 疫苗研究编码高百分比的HLA-II相关适应性表位，并且这些适应性表位 与HLA-II相关的非适应性相比，表位在HIV-1疫苗接受者中引起较弱的应答 表位因此，完全HLA-II非适应性HIV-1疫苗可能会导致更优化的免疫应答。 CD 4应答。这个项目将调查非适应和适应的功能和异质性 表位特异性CD 4应答，重点是识别HIV-1疫苗接受者中的表位特异性Tfh细胞 (Aim 1）。然后，该项目将确定这些CD 4反应对艾滋病毒特异性免疫缺陷病毒（HIV）的频率的贡献。 抗体和B细胞成熟（目的2）。通过表征CD 4对这些细胞的反应的功能， HLA-II相关表位并确定其对抗体产生的影响，我们的长期目标是 为未来的HIV-1疫苗研究提供可以提高HIV特异性抗体产生的策略， 持久保护免受HIV-1感染。 PI的拟议培训计划由其博士导师Paul Goepfert博士赞助。列入培训 计划的经验将帮助他在三个主要领域发展：1）对艾滋病毒进行严格的免疫学研究- 1，包括熟悉现有文献，批判性地评估已发表的研究， 在科学诚信和负责任的研究行为的原则培训; 2）生物信息学能力 技术和生物统计分析;和3）职业和专业发展，包括赠款写作， 期刊文章审查，通过演讲和手稿准备进行清晰的沟通，以及翻译 研究成果应用于临床。完成后，该培训计划将为PI提供基础 作为一名成功的医学科学家所必需的。他的最终职业目标是有一天领导一个 翻译研究团队，进行基于实验室的人类免疫学研究，以协助临床 预防和治疗各种传染病。

PROJECT SUMMARY The purpose of this NIH F30 application is to obtain support for the PI, Jacob Files, for his mentored research and career development for the next three years. These activities are part of his training requirements that are necessary for him to obtain his MD/PhD degree, and they will strengthen his potential to become a successful physician scientist. The major goal of this project is to develop his skills in order to study CD4+ T-cell responses (CD4 responses) in HIV-1 vaccine recipients using both immunological laboratory assays and computational techniques. The primary objective of the research proposal is to investigate the impact of HLA-II associated viral adaptation on CD4 responses in the setting of HIV-1 vaccination. CD4 responses have been found to play an important role in generating HIV-specific antibodies; therefore, an optimal CD4 response is likely to be an important component of future preventative HIV-1 vaccines. Our preliminary studies show that current HIV-1 vaccine studies encode a high percentage of HLA-II associated adapted epitopes and that these adapted epitopes elicit weaker responses in HIV-1 vaccine recipients compared to HLA-II associated non-adapted epitopes. Therefore, it is possible that a fully HLA-II non-adapted HIV-1 vaccine could lead to a more optimal CD4 response. This project will investigate the functionality and heterogeneity of the non-adapted and adapted epitope-specific CD4 responses, with a focus on identifying epitope-specific Tfh cells in HIV-1 vaccine recipients (Aim 1). Then, the project will determine the contribution of these CD4 responses to the frequency of HIV-specific antibodies and to B-cell maturation (Aim 2). By characterizing the functionality of the CD4 responses to these HLA-II associated epitopes and determining their impact on antibody production, our long-term objective is to inform future HIV-1 vaccine studies of strategies that can improve HIV-specific antibody production, leading to durable protection from HIV-1 infection. The proposed training plan for the PI is sponsored by his PhD mentor, Dr. Paul Goepfert. Included in the training plan are experiences that will help him develop in three major areas: 1) rigorous immunological research in HIV- 1, which includes developing familiarity with the existing literature, critically evaluating published studies, and training in principles of scientific integrity and responsible conduct of research; 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 applications. After completion, this training plan will provide the PI with the foundation necessary for a successful career as a physician scientist. His ultimate career goal is to one day lead a translational research team that performs laboratory-based human immunology research to assist in the clinical prevention and treatment of various infectious diseases.