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

剖析维持 HIV 特异性 CD8 T 细胞耗竭的信号

基本信息

批准号：
10330433
负责人：
Rachel Lena Rutishauser
金额：
$ 20.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-06 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330433
关键词：
Affect Animal Model Animals Antigens Area Award Blood Cells Blood specimen CD8-Positive T-Lymphocytes California Cell Differentiation process Cell physiology Cells Cellular biology Chronic Clinical Clinical Research Communicable Diseases Data Development Disease Disease remission Doctor of Philosophy Effector Cell Environment Flow Cytometry Funding Gatekeeping Genetic Transcription Goals HIV HIV Infections Human Immune response Immunity Immunologics Immunologist Immunology Individual Infection Infection Control Inflammation Inflammatory Interleukin-1 beta Intervention Laboratories Lymphoid Tissue MHC Class I Genes Malignant Neoplasms Measures Mediating Memory Mentored Patient-Oriented Research Career Development Award Mentors Monoclonal Antibodies Mus PD-1 blockade Pathogenesis Persons Phenotype Placebos Population Positioning Attribute Proliferating Regenerative capacity Regulation Research Research Personnel Research Priority San Francisco Schools Scientist Signal Transduction Specialist T cell differentiation T cell therapy T memory cell Therapeutic Intervention Tissues Toxic effect Training Translational Research United States National Institutes of Health Universities Vaccination Vaccine Design Vaccine Therapy Vaccines Virus WNT Signaling Pathway acute infection antiretroviral therapy base career chronic infection cohort cytokine effective therapy exhaust exhaustion immune activation immunomodulatory therapies inhibitor insight lymph nodes novel strategies novel therapeutics novel vaccines patient oriented research peripheral blood post intervention programs recruit regeneration function regeneration potential response single-cell RNA sequencing skills therapeutic development transcription factor transcriptome transcriptomics translational scientist

项目摘要

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.

项目总结

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Plasma-based antigen persistence in the post-acute phase of SARS-CoV-2 infection.

SARS-CoV-2 感染急性期后血浆抗原的持续存在。

DOI：
10.1101/2023.10.24.23297114
发表时间：
2023
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Peluso,MichaelJ;Swank,ZoeN;Goldberg,SarahA;Lu,Scott;Dalhuisen,Thomas;Borberg,Ella;Senussi,Yasmeen;Luna,MichaelA;Song,CelinaChang;Clark,Alexus;Zamora,Andhy;Lew,Megan;Viswanathan,Badri;Huang,Beatrice;Anglin,Khamal;Hoh,Reb
通讯作者：
Hoh,Reb

CD8 + T-cell responses in HIV controllers: potential implications for novel HIV remission strategies.