Impact of HIV on the T cell repertoire

HIV 对 T 细胞库的影响

• 批准号: 8110740
• 负责人: PAUL D BAUM
• 金额: $ 4.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-02 至 2012-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110740
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Adult; Aftercare; Age; Anti-Retroviral Agents; Applications Grants; Biological Assay; Biometry; Blood; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cell Count; Cells; Clinic; Clinical; Clinical Research; Clinical Trials Design; Cohort Studies; Collaborations; Data; Data Analyses; Development; Disease; Ethnic Origin; Event; Fostering; Foundations; Freezing; Future; Gender; General Hospitals; Genomics; Goals; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Immune; Immune response; Immune system; Immunocompetence; Immunologic Deficiency Syndromes; Immunology; Individual; Infection; Investigation; Kinetics; Knowledge; Laboratories; Lead; Letters; Link; Lymphocyte; Lymphocyte Count; Measurement; Measures; Mediating; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentorship; Methods; Normal Range; Opportunistic Infections; Pathogenesis; Patients; Play; Principal Investigator; Process; Prospective Studies; RNA; Reference Values; Relative (related person); Research; Research Personnel; Risk; Role; Sample Size; Sampling; San Francisco; Specificity; Specimen; Staging; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; Techniques; Testing; Time; Translational Research; Visit; alternative treatment; antiretroviral therapy; base; career; clinically relevant; design; experience; falls; human subject; novel; pathogen; peripheral blood; programs; receptor; reconstitution; skills

DESCRIPTION (provided by applicant): This K23 proposal is designed to foster my development as a translational researcher in the field of HIV immunology. My proposal is based on a novel assay, called AmpliCot, which I have developed to measure the diversity of the T cell receptor (TCR) repertoire. Although the TCR repertoire is a crucial determinant of the immune response, only now does AmpliCot make it possible to quantitatively measure changes in the repertoire diversity of clinical samples. Under the experienced mentorship of Dr. Joseph M. McCune and Dr. Steven Deeks, and with the guidance of a team of expert consultants in clinical laboratory medicine (Dr. Timothy Hamill), clinical trial design (Dr. Jeffrey Martin), and biostatistics (Dr. Mark Segal), I will obtain the practical knowledge necessary to bring my laboratory investigations to the clinic, launching my career in translational research. HIV infection is known to deplete the body's number of CD4+ T lymphocytes, but little is known about the effect of infection on the repertoire of TCR specificities. I will use AmpliCot to address the following aims: Aim 1: To optimize the AmpliCot assay for use with clinical specimens and to define the normal reference interval for repertoire diversity in healthy adults. Aim 2: To characterize the damage HIV inflicts on TCR repertoire diversity. Aim 3: To assess the degree to which antiretroviral therapy can reconstitute TCR repertoire diversity. The proposed studies are planned in collaboration with two large ongoing cohort studies of HIV-infected individuals at San Francisco General Hospital, thereby facilitating recruitment and retention of subjects, streamlining patient visits, and aiding data analysis. This proposal is a first step towards testing the hypothesis that HIV-infected patients are vulnerable to opportunistic infections because they have lost important TCR specificities and have "holes" in their repertoires. This research could play an important role in helping doctors determine the optimal time to begin treating HIV-infected patients with antiretroviral therapy, and the AmpliCot assay could be used in the future to evaluate the ability of alternative treatments to reconstitute the immune system of HIV-infected patients. The data and skills I will obtain in the K23 award will serve as a foundation for a subsequent prospective study (to be proposed in a future R01 grant application) to investigate whether measurements of lymphocyte receptor diversity can predict risks of opportunistic infections or other clinical events in HIV-infected patients.

描述（由申请人提供）：本 K23 提案旨在促进我作为 HIV 免疫学领域的转化研究人员的发展。我的提议基于一种名为 AmpliCot 的新型测定法，我开发该测定法是为了测量 T 细胞受体 (TCR) 库的多样性。尽管 TCR 库是免疫反应的关键决定因素，但直到现在 AmpliCot 才使得定量测量临床样本库多样性的变化成为可能。在 Joseph M. McCune 博士和 Steven Deeks 博士经验丰富的指导下，以及临床检验医学（Timothy Hamill 博士）、临床试验设计（Jeffrey Martin 博士）和生物统计学专家顾问团队的指导下（马克·西格尔博士），我将获得将实验室研究带到临床所需的实践知识，开启我的转化研究职业生涯。众所周知，HIV 感染会消耗体内 CD4+ T 淋巴细胞的数量，但人们对感染对 TCR 特异性的影响知之甚少。我将使用 AmpliCot 来实现以下目标： 目标 1：优化 AmpliCot 测定以用于临床样本，并定义健康成人库多样性的正常参考区间。目标 2：描述 HIV 对 TCR 库多样性造成的损害。目标 3：评估抗逆转录病毒疗法可以在多大程度上重建 TCR 库多样性。拟议的研究计划与旧金山综合医院正在进行的两项针对艾滋病毒感染者的大型队列研究合作，从而促进受试者的招募和保留，简化患者就诊并帮助数据分析。这项提议是检验 HIV 感染患者容易受到机会性感染的假设的第一步，因为他们失去了重要的 TCR 特异性，并且其库中存在“漏洞”。这项研究可以在帮助医生确定开始使用抗逆转录病毒疗法治疗 HIV 感染患者的最佳时间方面发挥重要作用，并且 AmpliCot 检测可以在未来用于评估替代疗法重建 HIV 免疫系统的能力。感染的患者。我将在 K23 奖项中获得的数据和技能将作为后续前瞻性研究（将在未来的 R01 拨款申请中提出）的基础，以调查淋巴细胞受体多样性的测量是否可以预测机会性感染或其他临床事件的风险在艾滋病毒感染者中。