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

基本信息

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
项目类别：
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

项目摘要

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 细胞反应的技能使用免疫实验室测定和计算方法对 HIV-1 疫苗接种者进行（CD4 反应）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。已发现 CD4 反应可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学科学家取得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。