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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：
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
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/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

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.

项目总结