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

项目总结 此NIH F30应用程序的目的是为他的指导性研究获得PI Jacob Files的支持 以及未来三年的职业发展。这些活动是他培训要求的一部分， 是他获得医学博士学位所必需的，他们将增强他成为成功人士的潜力 内科科学家。这个项目的主要目标是发展他的技能，以便研究CD4+T细胞反应 使用免疫学实验室检测和计算的HIV-1疫苗接受者的(CD4反应) 技巧。该研究计划的主要目的是调查人类白细胞抗原II相关病毒的影响。 HIV-1疫苗接种背景下对CD4反应的适应。已发现CD4反应在一种 在产生HIV特异性抗体方面发挥重要作用；因此，最佳的CD4应答可能是 未来预防性艾滋病毒-1疫苗的重要组成部分。我们的初步研究表明，目前的HIV-1 疫苗研究编码了很高比例的与人类白细胞抗原II相关的适应表位，这些适应表位 与人类白细胞抗原II相关的非适应性反应相比，HIV-1疫苗接受者的表位诱导的应答较弱 表位。因此，一种完全不适应人类白细胞抗原II的HIV-1疫苗可能会导致更理想的 CD_4应答。这个项目将调查非改编和改编的功能和异构性 HIV-1疫苗接受者中表位特异性的CD4应答，重点是识别表位特异性的Tfh细胞 (目标1)。然后，该项目将确定这些CD4反应对HIV特异性频率的贡献 抗体和B细胞成熟(目标2)。通过表征CD4对这些疾病的反应的功能 和确定它们对抗体产生的影响，我们的长期目标是 向未来的艾滋病毒-1疫苗研究通报可改善艾滋病毒特异性抗体产生的策略，导致 持久保护免受HIV-1感染。 建议的PI培训计划是由他的博士导师Paul Goepfert博士赞助的。包括在培训中 计划是帮助他在三个主要领域发展的经验：1)严格的艾滋病毒免疫学研究- 1，包括熟悉现有文献，批判性地评估已发表的研究，以及 培训科学诚信原则和负责任的研究行为；2)生物信息学方面的能力 技术和生物统计分析；以及3)职业和专业发展，包括拨款申请， 期刊文章审阅，通过演示和手稿准备进行清晰的沟通，以及翻译 研究成果转化为临床应用。完成后，本培训计划将为PI提供基础 成为一名成功的内科科学家所必需的。他的最终职业目标是有一天领导一个 翻译研究团队，执行基于实验室的人类免疫学研究，以协助临床 防治各种传染病。

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.