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

HIV-1 疫苗接种中 HLA-II 适应对 CD4 T 细胞和 Tfh 反应的影响

• 批准号: 10254574
• 负责人: Jacob Files
• 金额: $ 3.93万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254574
• 关键词: ALVAC; Acute; Affect; Alleles; Amino Acids; Antibodies; Antibody Formation; Antibody Response; Antigens; Area; Autologous; B-Lymphocytes; BLR1 gene; Binding; Bioinformatics; Biological Assay; Biometry; CD4 Positive T Lymphocytes; Cell Line; Cell Maturation; Cells; Chronic; Clinical; Communicable Diseases; Communication; Competence; Computational Technique; Data; Development; Disease Progression; Doctor of Philosophy; Effector Cell; Epidemic; Epitopes; Exhibits; Familiarity; Flow Cytometry; Foundations; Frequencies; Future; Generations; Genetic Polymorphism; Goals; Grant; HIV; HIV Envelope Protein gp120; HIV Vaccine Trials Network; HIV vaccine; HIV-1; HIV-1 vaccine; Heterogeneity; Human; IL4 gene; Immune; Immune response; Immune system; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Switch Recombination; Immunologics; Immunology; In Vitro; Individual; Infection; Laboratories; Lead; Literature; Manuscripts; Mentors; OX40; Patients; Peptides; Peripheral; Phenotype; Physicians; Play; Preparation; Prevention; Process; Production; Publishing; Research; Research Proposals; Role; Sampling; Scientist; Site; T cell response; T-Lymphocyte Subsets; TNFSF5 gene; Techniques; Testing; Training; Translational Research; United States National Institutes of Health; Up-Regulation; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Viral Load result; Writing; antiretroviral therapy; base; career; career development; clinical application; cytokine; efficacy study; env Gene Products; experience; immunogenic; improved; insight; interest; interleukin-21; journal article; pressure; programmed cell death ligand 1; research and development; response; responsible research conduct; single-cell RNA sequencing; skills; vaccine response; vaccine trial; vaccine-induced antibodies

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.

项目摘要 该NIH F30申请的目的是为他的指导研究获得对PI，Jacob文件的支持 和未来三年的职业发展。这些活动是他的培训要求的一部分 他获得他的MD/博士学位所必需的，他们将增强他成为成功的潜力 医师科学家。该项目的主要目的是发展他的技能，以研究CD4+ T细胞回答 （CD4反应）使用免疫实验室和计算的HIV-1疫苗接种者 技术。研究建议的主要目的是研究HLA-II相关病毒的影响 在HIV-1疫苗接种的情况下，对CD4反应的适应。发现CD4响应播放 在产生HIV特异性抗体中的重要作用；因此，最佳CD4响应可能是 未来预防性HIV-1疫苗的重要组成部分。我们的初步研究表明当前的HIV-1 疫苗研究编码高百分比的HLA-II相关的适应性表位，并且这些适应 与HLA-II相关的非适应性相比 表位。因此，完全HLA-II非适应性HIV-1疫苗可能导致更优化的 CD4响应。该项目将调查未适应和适应的功能和异质性 表位特异性CD4反应，重点是鉴定HIV-1疫苗接种者中的表位特异性TFH细胞 （目标1）。然后，该项目将确定这些CD4响应对HIV特异性频率的贡献 抗体和B细胞成熟（AIM 2）。通过表征CD4对这些响应的功能 HLA-II相关的表位并确定其对抗体生产的影响，我们的长期目标是 告知未来的HIV-1疫苗研究可以改善HIV特异性抗体产生的策略，从而导致 防止HIV-1感染的耐用保护。 PI的拟议培训计划由他的博士导师Paul Goepfert博士赞助。包括在培训中 计划是有助于他在三个主要领域发展的经验：1） 1，包括对现有文献的熟悉，对已发表的研究进行严格评估，以及 培训科学完整性和负责任的研究的原则； 2）生物信息的能力 技术和生物统计分析； 3）职业和专业发展，包括赠款写作， 期刊文章评论，通过演示和手稿准备的清晰沟通以及翻译 临床应用的研究结果。完成后，该培训计划将为PI提供基金会 作为医师科学家成功的职业生涯所必需的。他的最终职业目标是有一天领导 进行基于实验室的人类免疫学研究以协助临床的转化研究团队 预防和治疗各种传染病。