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

项目摘要 这是一份K23奖的申请，申请人是Rachel Rutishauser博士，医学博士，博士，传染病研究员， 加州大学，旧金山弗朗西斯科，她正在建立自己作为一个年轻的研究人员在病人- 艾滋病免疫学的研究。她的目标是将她的博士研究生院背景应用于基础CD 8 + T细胞生物学研究HIV保护性和功能失调性免疫反应的机制 感染全世界有近4000万人感染艾滋病毒， 缓解或治愈是NIH高度优先的研究领域。许多方法建议通过引出 保护HIV特异性CD 8 + T细胞。然而，为了有效，这些疗法需要克服艾滋病毒- 特异性CD 8 + T细胞耗竭。衰竭被定义为抗原再生能力的丧失- 特异性CD 8 + T细胞增殖并产生功能性效应细胞。K23奖将提供博士。 Rutishauser在研究HIV特异性CD 8 + T细胞耗竭如何受以下因素调节的支持下：（1）记忆 CD 8 + T细胞相关的转录程序，（2）组织微环境，和（3）慢性炎症。 具体来说，她将进行表型，功能和单细胞转录组学分析艾滋病毒特异性 来自30名HIV感染者外周血、淋巴结和肠道组织的MHC I类四聚体+CD 8 + T细胞， 她将从基于UCSF的SCOPE队列中招募的感染者，来自三个临床组： 自然控制感染的人（控制者），以及非控制者，接受和不接受抗逆转录病毒治疗 治疗（ART）。她还将确定减少慢性炎症是否可以增强HIV特异性CD 8 + T细胞 通过利用来自NIH资助的正在进行的临床研究（NCT 02272946）的外周血样本， 接受IL-1β抑制剂canakinumab给药的ART抑制HIV感染者。实现 为了实现这些目标，Rutishauser博士将由HIV转化免疫学家Peter Hunt博士共同指导， 艾滋病免疫激活机制方面的专家约瑟夫·迈克·麦库姆博士是一位实验室科学家， 在艾滋病发病机制方面有几项基本发现的史蒂文·迪克斯博士， 艾滋病治疗领域，和马克安塞尔博士，免疫学家与T细胞分化的专业知识。通过集中 指导培训和课程计划，候选人将发展临床研究的高级技能， 人翻译免疫学和单细胞转录分析。这些研究的结果 预计将直接相关的艾滋病毒治疗研究和广泛适用于开发治疗其他 出现耗尽的抗原特异性CD 8 + T细胞的疾病状态，如其他慢性感染， 癌最终，这里概述的培训和研究计划将支持Rutishauser博士过渡 从基础免疫学家和临床传染病专家到转化研究人员 具备追求独立职业的技能，专注于阐明以下基本原则： CD 8 + T细胞生物学，并为传染病的治疗和疫苗的开发提供信息。

Project Summary This is an application for a K23 award for Dr. Rachel Rutishauser, MD, PhD, a fellow in Infectious Diseases at the University of California, San Francisco who 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.