Dissecting the signals that maintain HIV-specific CD8+ T cell exhaustion - administrative supplement

家长助学金项目总结 这是一份K23奖项的申请书，授予雷切尔·鲁蒂肖瑟博士，医学博士，博士，正在确立自己的地位 青年研究员，从事以病人为中心的艾滋病毒免疫学研究。她的目标是申请她的博士研究生 有CD8+T细胞生物学基础的学校背景，研究保护和 HIV感染中的免疫功能障碍反应。全世界有近4000万人感染了 艾滋病毒和确定诱导艾滋病毒缓解或治愈的干预措施是国立卫生研究院的一个高度优先的研究领域。 许多方法建议通过诱导保护性的HIV特异性CD8+T细胞来做到这一点。然而，为了成为 有效的这些疗法需要克服HIV特异性CD8+T细胞的耗尽。精疲力竭的定义是 抗原特异性CD8+T细胞增殖和产生功能性的再生能力丧失 效应细胞。这项K23奖项将为Rutishauser博士提供支持，以探索HIV特异性CD8如何 +T细胞耗竭受以下因素的调节：(1)记忆CD8+T细胞相关的转录程序，(2)组织 微环境；(3)慢性炎症。具体地说，她将表演表型、功能性和 HIV特异性MHC-I类四聚体+CD8+T细胞的单细胞转录分析 她将从加州大学旧金山分校招募30名艾滋病毒感染者的血液、淋巴结和肠道组织- 基于三个临床组的范围队列：自然控制感染的个人(控制者)，AS 以及接受和停止抗逆转录病毒治疗(ART)的非控制者。她还将确定是否减少慢性 炎症可通过利用来自以下人群的外周血液样本增强HIV特异性CD8+T细胞功能 美国国立卫生研究院资助的一项正在进行的临床研究(NCT02272946)，研究对象是患有抗逆转录病毒药物的艾滋病毒感染者 给予IL-1β抑制剂Canakinumab。为了实现这些目标，Rutishauser博士将得到共同指导 彼得·亨特博士，艾滋病毒翻译免疫学家和艾滋病毒免疫机制专家 激活，约瑟夫·迈克·麦库恩博士，一位以实验室为基础的科学家，他已经做出了几项基本的 关于艾滋病毒发病机制的发现，艾滋病毒治疗领域的领导者史蒂文·迪克斯博士和马克·安塞尔博士， 一位在T细胞分化方面有专长的免疫学家。通过有重点的辅导性培训和 在课程工作中，候选人将发展临床研究、人类翻译方面的高级技能 免疫学和单细胞转录分析。这些研究的结果预计为 与HIV治愈研究直接相关，并广泛适用于开发其他疾病的治疗方法 出现耗尽的抗原特异性CD8+T细胞的状态，如其他慢性感染和癌症。 最终，这里概述的培训和研究计划将支持Rutishauser博士从 从基础免疫学家和临床传染病专家到翻译研究人员 具备追求独立职业的技能，专注于阐明基本原则 研究CD8+T细胞生物学，并为传染病的治疗和疫苗的发展提供信息。

PROJECT SUMMARY OF PARENT GRANT This is an application for a K23 award for Dr. Rachel Rutishauser, MD, PhD, is establishing herself as a young investigator in patient-oriented studies of HIV immunology. Her goal is to apply her PhD graduate school background in basic CD8+ T cell biology to study the mechanisms that underlie protective and dysfunctional immune responses in HIV infection. Nearly forty million people worldwide are infected with HIV and identifying interventions to induce HIV remission or cure is an NIH high priority research area. Many approaches propose to do so by eliciting protective HIV-specific CD8+ T cells. However, in order to be effective, these therapies need to overcome HIV-specific CD8+ T cell exhaustion. Exhaustion is defined as a loss in the regenerative capacity of antigen-specific CD8+ T cells to proliferate and generate functional effector cells. This K23 award will provide Dr. Rutishauser with the support to explore how HIV-specific CD8 + T cell exhaustion is regulated by: (1) memory CD8+ T cell-associated transcriptional programs, (2) tissue microenvironments, and (3) chronic inflammation. Specifically, she will perform phenotypic, functional, and single-cell transcriptomic analysis of HIV-specific MHC Class I tetramer+ CD8+ T cells from the peripheral blood, lymph node, and gut tissue of thirty HIV-infected individuals who she will recruit from the UCSF- based SCOPE cohort from three clinical groups: individuals who naturally control infection (controllers), as well as non-controllers on and off of antiretroviral therapy (ART). She will also determine if reducing chronic inflammation can enhance HIV-specific CD8+ T cell function by leveraging peripheral blood samples from an ongoing NIH-funded clinical study (NCT02272946) of ART-suppressed HIV-infected individuals who are administered the IL-1β inhibitor, canakinumab. To achieve these goals, Dr. Rutishauser will be co-mentored by Dr. Peter Hunt, an HIV translational immunologist and expert in the mechanisms of HIV immune activation, Dr. Joseph Mike McCune, a laboratory-based scientist who has made several fundamental discoveries about HIV pathogenesis, Dr. Steven Deeks, a leader in the HIV cure field, and Dr. Mark Ansel, an immunologist with expertise in T cell differentiation. Through a focused program of mentored training and coursework, the candidate will develop advanced skills in clinical research, human translational immunology, and single-cell transcriptional analysis. The results of these studies are anticipated to be directly relevant to HIV cure research and widely applicable to developing treatments for other disease states in which exhausted antigen-specific CD8+ T cells arise, such as other chronic infections and cancer. Ultimately, the training and research plans outlined here will support Dr. Rutishauser as she transitions from being a basic immunologist and clinical infectious disease specialist to being a translational researcher equipped with the skills to pursue an independent career focused on elucidating the fundamental principles of CD8+ T cell biology and informing the development of therapeutics and vaccines for infectious diseases.