Impact of HIV on the T cell repertoire

HIV 对 T 细胞库的影响

• 批准号: 7619094
• 负责人: PAUL D BAUM
• 金额: $ 12.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619094
• 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）：该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。我的建议基于一种称为Amplicot的新颖测定法，我已经开发出来衡量T细胞受体（TCR）曲目的多样性。尽管TCR曲目是免疫反应的关键决定因素，但直到现在，放大器才有可能定量测量临床样品的曲目多样性的变化。在约瑟夫·M·麦克辛（Joseph M. （马克·塞加尔（Mark Segal）博士），我将获得必要的实践知识，以将我的实验室调查带到诊所，从而启动转化研究的职业。已知HIV感染会耗尽人体CD4+ T淋巴细胞的数量，但对感染对TCR特异性曲目的影响知之甚少。我将使用放大器来解决以下目的：目标1：优化与临床标本一起使用的扩增器测定法，并定义健康成年人的正常参考间隔。目标2：描述艾滋病毒对TCR曲目多样性造成的损害。目标3：评估抗逆转录病毒疗法可以重建TCR曲目多样性的程度。拟议的研究计划与旧金山综合医院的两项大型正在进行的HIV感染者的持续研究研究，从而促进受试者的招募和保留，简化患者访问以及有助于数据分析。该提案是检验假设的第一步，即感染HIV的患者容易受到机会性感染的影响，因为他们失去了重要的TCR特异性并在其曲目中具有“孔”。这项研究可能在帮助医生确定开始治疗抗逆转录病毒疗法的HIV患者的最佳时间方面发挥重要作用，并且将来可以使用扩增子测定法来评估替代治疗的能力，以重新建立HIV的免疫系统。感染的患者。我将在K23奖中获得的数据和技能将成为随后的前瞻性研究（将在未来R01赠款应用中提出的）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的风险或其他临床事件的风险在HIV感染的患者中。