Harnessing Stem-Like CD8 T Cells for Immunotherapies to Eradicate HIV Reservoirs

利用干细胞样 CD8 T 细胞进行免疫疗法来根除 HIV 病毒库

基本信息

批准号：
10447569
负责人：
Chen Yao
金额：
$ 49.2万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-08 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10447569
关键词：
AIDS/HIV problem Acetylation Acute Adopted Adoptive Cell Transfers Affect Aftercare Age Animal Model Animals B-Lymphocytes BLR1 gene CAR T cell therapy CD8-Positive T-Lymphocytes CD8B1 gene CRISPR screen Cancer Patient Cells Cellular Immunity Cellular immunotherapy Chronic Clinical Research Cytolysis DNA Data Disease remission Epigenetic Process Exhibits Foundations Frequencies Future Gene Expression Profile Genetic Transcription HIV HIV Infections Helper-Inducer T-Lymphocyte Histone Acetylation Histones Human Immune Immunity Immunotherapy Infection Interruption Lymphocytic choriomeningitis virus Lysine Macaca Macaca mulatta Malignant Neoplasms Mediating Mus PD-L1 blockade Pathway interactions Patients Persons Pharmaceutical Preparations Phenotype Population Research Risk SIV STEM program Sampling Shock Site T cell differentiation T-Lymphocyte T-Lymphocyte Subsets Technology Testing Therapeutic Effect Viral Viremia Virus Virus Diseases Virus Replication anti-PD-L1 antiretroviral therapy antiviral immunity base cancer immunotherapy chimeric antigen receptor chronic infection comorbidity cost epigenetic drug epigenome exhaust exhaustion immune checkpoint blockade in vivo infected B cell insight interest latent HIV reservoir model design novel novel strategies overexpression pre-clinical research programs response stem therapeutic vaccine transcription factor transcriptome transcriptomics tumor viral rebound

项目摘要

Project Abstract Although combination antiretroviral therapy (cART) effectively suppresses human immunodeficiency virus (HIV) replication, it does not cure HIV infection and requires costly lifelong treatment. A major challenge for curing HIV infection is the long-lived latent HIV reservoir, which evades immune recognition and is responsible for viral rebound shortly after interruption of cART. Substantial research efforts have focused on eliminating latently infected cells through so-called “shock and kill” strategy, which reactivates latent HIV using latency- reversing agents (LRAs) to allow for the “kill” by cytolysis or immune-mediated clearance. Particularly, eradication of theHIV reservoir by anti-HIV T cells, which maintain antiviral immunity in patients as a “living” drug, presents a promising strategy to either fully resolve the infection or maintain long-term control without cART treatment. However, clearance of the HIV reservoir by T-cell based immunotherapy remains challenging because of 1) T- cell exhaustion, 2) the need of lifelong anti-HIV immunity to replace cART, 3) sanctuary sites like B cell follicles that exclude most HIV-specific CD8 T cells, and 4) unclear impact of LRAs, most of which target epigenetic pathways, on the function and differentiation of antiviral CD8 T cells in vivo. We and others have recently characterized a stem-like CD8 T cell subset in chronic lymphocytic choriomeningitis virus (LCMV), simian immunodeficiency virus (SIV), and HIV infections, as well as in mouse and human tumors. Compared to terminally exhausted CD8 T cells, stem-like CD8 T cells are less exhausted, mediate long-term immunity, and respond more potently after treatment of immunotherapies in animals and human. In chronic LCMV, SIV, and HIV infections, these cells express CXCR5, migrate to B cell follicles and kill infected T follicular helper cells, a major latent reservoir of HIV and SIV. In addition, frequency of these cells inversely correlates with viremia of SIV or HIV. Most recently, we showed that the single-cell transcriptomic and epigenetic profiles of stem-like CD8 T cells are distinct from other CD8 subsets generated after acute or chronic LCMV infection. In addition, we identified a transcriptional program involving transcription factor TOX that is essential for stem-like CD8 T cell differentiation and the long-term persistence of antiviral CD8 T cells during chronic viral infection. Here, I will determine the transcriptional and epigenetic programs of stem-like CD8 T cells required for optimal T-cell based immunotherapy against HIV. I will use animal models of chronic LCMV and SIV infections as well as samples from HIV patients, and employ cutting-edge technologies, including single-cell profiling of T-cell transcriptomes and epigenomes, CRISPR/Cas9 screening, and chimeric antigen receptor (CAR) T-cell therapy, to determine how “shock” by epigenetic modifying LRAs affects the program and antiviral immunity of stem-like CD8 T cells and whether transcriptional and epigenetic programs of stem-like CD8 T cells can be adopted to enhance the “kill” of the HIV reservoir by T-cell based immunotherapies. The results from this study will build the foundation for novel immunotherapies that achieve long-term remission from HIV infection without a need for cART.

项目摘要尽管联合抗逆转录病毒疗法（cART）可以有效抑制人类免疫缺陷病毒（HIV）复制，它不能治愈艾滋病毒感染，并且需要昂贵的终身治疗，这是艾滋病毒感染者面临的主要挑战。治愈艾滋病毒感染的方法是长期潜伏的艾滋病毒储存库，它逃避免疫识别并负责大量研究工作集中于消除 cART 中断后不久的病毒反弹。通过所谓的“休克和杀伤”策略，利用潜伏期重新激活潜伏的艾滋病毒逆转剂（LRA）可通过细胞溶解或免疫介导的清除来“杀死”，特别是根除。抗 HIV T 细胞作为一种“活”药物维持患者的抗病毒免疫力，从而破坏了 HIV 储存库。这是一种有希望的策略，可以完全解决感染或在不进行 cART 治疗的情况下保持长期控制。然而，通过基于 T 细胞的免疫疗法清除 HIV 储存库仍然具有挑战性，因为 1) T- 细胞耗竭，2) 需要终生抗 HIV 免疫来替代 cART，3) B 细胞滤泡等避难所排除了大多数 HIV 特异性 CD8 T 细胞，4) LRA 的影响尚不清楚，其中大多数针对表观遗传我们和其他人最近对体内抗病毒 CD8 T 细胞的功能和分化进行了研究。表征了慢性淋巴细胞脉络膜脑膜炎病毒（LCMV）中的干细胞样 CD8 T 细胞亚群，猿猴免疫缺陷病毒（SIV）和艾滋病毒感染，以及小鼠和人类肿瘤中的比较。最终耗尽的 CD8 T 细胞，干细胞样 CD8 T 细胞较少耗尽，介导长期免疫，并且在动物和人类的慢性 LCMV、SIV 和免疫疗法治疗后，其反应更有效。 HIV 感染时，这些细胞表达 CXCR5，迁移到 B 细胞滤泡并杀死受感染的滤泡辅助 T 细胞，此外，这些细胞的出现频率与病毒血症呈负相关。最近，我们展示了干细胞样 CD8 的单细胞转录组和表观遗传学特征。 T 细胞与急性或慢性 LCMV 感染后产生的其他 CD8 亚群不同。确定了一个涉及转录因子 TOX 的转录程序，该转录因子对于干细胞样 CD8 T 细胞至关重要慢性病毒感染期间抗病毒 CD8 T 细胞的分化和长期持续性。确定最佳 T 细胞所需的干细胞样 CD8 T 细胞的转录和表观遗传程序我将使用慢性 LCMV 和 SIV 感染的动物模型以及样本。来自 HIV 患者的数据，并采用尖端技术，包括 T 细胞转录组的单细胞分析和表观基因组、CRISPR/Cas9 筛选和嵌合抗原受体 (CAR) T 细胞疗法，以确定表观遗传修饰 LRA 的“休克”如何影响干细胞样 CD8 T 细胞的程序和抗病毒免疫是否可以采用干细胞样 CD8 T 细胞的转录和表观遗传程序来增强通过基于 T 细胞的免疫疗法“杀死”HIV 病毒库这项研究的结果将为我们奠定基础。无需 cART 即可实现 HIV 感染长期缓解的新型免疫疗法。