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: 10406917
• 负责人: Jacob Files
• 金额: $ 4.41万
• 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/10406917
• 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; Vaccinee; 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.

项目概要 此 NIH F30 申请的目的是获得对 PI Jacob Files 指导研究的支持 以及未来三年的职业发展。这些活动是他的培训要求的一部分 他获得医学博士/博士学位所必需的，并且它们将增强他成为成功人士的潜力 医师科学家。该项目的主要目标是培养他研究 CD4+ T 细胞反应的技能 （CD4 反应）在 HIV-1 疫苗接种者中使用免疫实验室测定和计算 技术。该研究计划的主要目的是调查 HLA-II 相关病毒的影响 HIV-1 疫苗接种环境中 CD4 反应的适应。 CD4 反应已被发现发挥 在产生艾滋病毒特异性抗体方面发挥重要作用；因此，最佳的 CD4 反应可能是 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，目前的 HIV-1 疫苗研究编码了高比例的 HLA-II 相关适应表位，并且这些适应表位 与 HLA-II 相关的非适应者相比，表位在 HIV-1 疫苗接种者中引起的反应较弱 表位。因此，完全 HLA-II 不适应的 HIV-1 疫苗可能会带来更优化的结果。 CD4反应。该项目将研究非适应和适应的功能和异质性 表位特异性 CD4 反应，重点是识别 HIV-1 疫苗接种者中表位特异性 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 对这些反应的功能 HLA-II 相关表位并确定它们对抗体产生的影响，我们的长期目标是 为未来的 HIV-1 疫苗研究提供可改善 HIV 特异性抗体产生的策略，从而导致 持久保护免受 HIV-1 感染。 PI 拟议的培训计划由他的博士导师 Paul Goepfert 博士赞助。包含在培训中 计划中的经验将帮助他在三个主要领域发展：1）针对艾滋病毒的严格免疫学研究 1，包括熟悉现有文献，批判性地评估已发表的研究，以及 科学诚信原则和负责任的研究行为培训； 2）生物信息学能力 技术和生物统计分析； 3）职业和专业发展，包括资助写作， 期刊文章审阅，通过演示和稿件准备进行清晰的沟通，以及翻译 研究成果到临床应用。完成后，该培训计划将为PI提供基础 作为一名医师科学家的成功职业生涯所必需的。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。