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：
10653946
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/10653946
关键词：
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 Exclusion Exhibits Foundations Frequencies Future Gene Expression Profile Genetic Transcription HIV HIV Infections HIV/AIDS Helper-Inducer T-Lymphocyte Histone Acetylation Histones Human Immune Immune Evasion 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 Sampling Shock Site T cell differentiation T cell therapy T-Lymphocyte T-Lymphocyte Subsets Technology Testing Therapeutic Effect Viral Viremia Virus Virus Diseases Virus Replication anti-PD-L1 antiretroviral therapy antiviral immunity cancer immunotherapy cell motility 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 migration 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.

项目摘要尽管抗逆转录病毒疗法（CART）有效地抑制了人类免疫缺陷病毒（艾滋病毒）复制，它不能治愈艾滋病毒感染，需要昂贵的终身治疗。一个主要的挑战治愈艾滋病毒感染是长期寿命的潜在艾滋病毒水库，可逃避免疫识别并负责对于手推车中断后不久，病毒反弹。大量的研究工作重点是消除通过所谓的“冲击和杀戮”策略，潜在感染细胞，该策略使用潜伏期重新激活潜在的HIV。逆转剂（LRAS）允许通过细胞解析或免疫介导的清除允许“杀死”。特别是根除抗HIV T细胞的HHIV储存剂，这些抗病毒免疫作为“活着”药物的抗病毒免疫，有望在没有卡车治疗的情况下完全解决感染或保持长期控制的承诺策略。但是，由于1）T- 细胞疲惫，2）需要终身反HIV免疫来代替购物车，3）像B细胞一样的避难所。排除大多数HIV特异性CD8 T细胞，4）LRA的不明确影响，其中大多数靶向表观遗传学途径，关于体内抗病毒CD8 T细胞功能和分化的途径。我们和其他人最近有表征了慢性淋巴细胞绒毛膜炎病毒（LCMV）中的茎状CD8 T细胞子集免疫缺陷病毒（SIV）和HIV感染以及小鼠和人类肿瘤。相比末端耗尽的CD8 T细胞，茎状的CD8 T细胞耗尽较少，培养基长期免疫力，并且在动物和人类的免疫疗法治疗后，反应更大。在慢性LCMV，SIV和 HIV感染，这些细胞表达CXCR5，迁移到B细胞上，杀死感染的T卵泡辅助细胞A，A 艾滋病毒和SIV的主要潜在水库。另外，这些细胞的频率与 SIV或HIV。最近，我们表明了茎状CD8的单细胞转录组和表观遗传学特征 T细胞不同于急性或慢性LCMV感染后产生的其他CD8子集。另外，我们确定了涉及转录因子TOX的转录程序，该程序对于茎样CD8 T细胞必不可少慢性病毒感染期间抗病毒CD8 T细胞的分化和长期持久性。在这里，我会的确定最佳基于T细胞所需的茎状CD8 T细胞的转录和表观遗传程序免疫疗法对艾滋病毒。我将使用慢性LCMV和SIV感染的动物模型以及样品来自HIV患者并采用尖端技术，包括T细胞转录组的单细胞分析和Epepeemonomes，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“冲击”如何影响茎状CD8 T细胞的程序和抗病毒免疫力以及是否可以采用类似茎状CD8 T细胞的转录和表观遗传程序来增强基于T细胞的免疫疗法对HIV水库的“杀死”。这项研究的结果将建立基础对于新的免疫疗法，可以从HIV感染中长期缓解而无需购物。