Viral adaptation to CD4 T cell responses and the impact on HIV immunity

病毒对 CD4 T 细胞反应的适应及其对 HIV 免疫的影响

• 批准号: 10202395
• 负责人: Nathaniel Bernard Erdmann
• 金额: $ 14.9万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-14 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202395
• 关键词: Acute; Affinity; Alleles; Amino Acids; Antibody Response; Antigens; Antiviral Agents; Area; Automobile Driving; B cell differentiation; Biological; Biological Assay; Blood; Blood specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Line; Cell Maturation; Cell physiology; Characteristics; Chronic; Clinical; Clinical Course of Disease; Data; Development; Disease; Disease Progression; Educational Curriculum; Ensure; Epitopes; Frequencies; Future; Genetic Polymorphism; Genotype; Goals; HIV; HIV Infections; HIV vaccine; HIV-1; Helper-Inducer T-Lymphocyte; Heterosexuals; Immune; Immune response; Immune system; Immunity; Immunologics; Impairment; Individual; Investigation; Knowledge; Link; Lymphocyte; Lymphoid Tissue; Mediating; Mentorship; Mutation; Organ Donor; Outcome; Pathogenesis; Patients; Pattern; Peripheral Blood Lymphocyte; Persons; Phenotype; Population; Property; Research; Role; Sorting - Cell Movement; Source; Spleen; T cell receptor repertoire sequencing; T cell response; T-Cell Receptor; T-Lymphocyte Epitopes; T-Lymphocyte Subsets; T-cell receptor repertoire; Testing; Time; Tissues; Vaccination; Vaccine Design; Vaccines; Viral; Viral Load result; Virus; Virus Diseases; antigen binding; clinically relevant; cohort; cytotoxic; design; effector T cell; experimental study; immune function; immunogenicity; in vivo; lymph nodes; neutralizing antibody; pathogen; peripheral blood; pressure; programs; receptor; receptor expression; response; skill acquisition; transcriptome sequencing; transmission process; vaccine development; viral transmission

ABSTRACT Robust CD4 T cell responses are likely to be critical for any protective HIV vaccine through their multifaceted support of immune effectors, but as the primary targets of HIV infection their contribution to host immunity has been relatively understudied. We have recently demonstrated CD4 T cell immune responses are capable of driving viral adaptation, but the mechanism of this activity and its relevance to overall disease pathogenesis is unknown. A CD4 T cell subset, the T follicular helper cell (Tfh), has become a focus of investigation for its role in B cell differentiation and maturation as well as its facilitation of pathogen-specific high-affinity neutralizing antibody responses. CD4 T cells also have cytotoxic potential, a phenotype we have shown is compromised by single amino acid changes in viral epitopes suggesting a role in viral escape. We hypothesize viral adaptation compromises the immunologic functions of CD4 T cells resulting in a survival benefit for HIV and impacting the clinical course of disease. We will test this hypothesis in three separate aims: Specific Aim 1: Through TCR sequencing, determine the effects of viral adaptation on CD4 T cells ability to bind antigen and appropriately activate in response to stimulation. Specific Aim 2: Define the impact of viral adaptation on CD4 T cell effector functions as expressed by cytotoxic capacity and expansion of the Tfh phenotype. Specific Aim 3: Determine whether persons infected with highly adapted virus have accelerated HIV-1 clinical disease progression. The proposed aims will reveal the mechanism underlying viral adaptation to CD4 T cell immune pressure and the impact on disease. To support these efforts, I have developed a collaborative program that will provide access to primary tissues from deceased-donors, offering a unique opportunity to corroborate findings observed in peripheral blood samples with those from tissue-derived lymphocytes. The mentorship team combines a strong record of trainee development and expertise in the areas most relevant to the planned experiments. I also present a curriculum designed to enhance my immunologic knowledge, technical repertoire, statistical knowledge and professional development. The proposal will facilitate development of the skills necessary to identify clinically relevant research questions and advance the understanding of immunity to HIV and other chronic viral infections.

摘要 强大的CD4T细胞反应可能是任何保护性HIV疫苗的关键，通过其多方面的 免疫效应器的支持，但作为艾滋病毒感染的主要目标，它们对宿主免疫的贡献 研究相对较少。我们最近证明了CD4T细胞免疫反应能够 驱动病毒适应，但这种活动的机制及其与整体疾病发病机制的相关性是 未知。CD4T细胞亚群，T滤泡辅助细胞(TFH)已成为研究的重点 它所扮演的角色 B细胞分化成熟及其对病原体特异性高亲和力中和的促进作用 抗体反应。 CD4T细胞也具有细胞毒潜力，我们已经显示的一种表型受到 病毒表位中单一氨基酸的变化提示了病毒逃逸的作用。我们假设病毒 适应损害CD4T细胞的免疫功能，从而使患者的生存受益 艾滋病毒和影响临床病程。我们将从三个不同的目标来检验这一假设： 具体目标1：通过TCR测序，确定病毒适应对CD4T细胞的影响 结合抗原并对刺激作出反应而适当激活的能力。 具体目标2：确定病毒适应对CD4T细胞效应器功能的影响 Tfh表型的细胞毒能力和扩增能力。 具体目标3：确定感染高度适应病毒的人是否加速了艾滋病毒-1 临床疾病进展。 拟议的目标将揭示病毒适应CD4T细胞免疫压力和 对疾病的影响。为了支持这些努力，我开发了一个协作计划，将提供 获取已故捐赠者的初级组织，提供了一个独特的机会来证实研究结果 在组织来源淋巴细胞的外周血样中观察。导师团队 结合学员发展的良好记录和与计划最相关的领域的专业知识 实验。我还提出了一个课程，旨在增强我的免疫学知识，技术 曲目、统计知识和专业发展。这项建议将有助发展 识别临床相关研究问题和提高对免疫力的理解所需的技能 艾滋病毒和其他慢性病毒感染。