Targeting HIV-specific T cell differentiation programs to enhance post-treatment control of HIV

针对 HIV 特异性 T 细胞分化计划，增强 HIV 治疗后控制

• 批准号: 10483785
• 负责人: Rachel Lena Rutishauser
• 金额: $ 79.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-19 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10483785
• 关键词: Aftercare; Animal Model; Antigens; Autologous; Bar Codes; Basic Science; Blood specimen; CAR T cell therapy; CD8-Positive T-Lymphocytes; Cancer Control; Cells; Chronic; Clinical; Clinical Trials; Collaborations; Cytometry; Development; Disease; Effector Cell; Funding; Future; Gene Expression Profiling; Genetic Engineering; Genetic Transcription; Goals; HIV; HIV Infections; Human; Human Engineering; In Vitro; Individual; Infection; Infusion procedures; Interruption; Intervention; Knowledge; Lymphoid Tissue; MHC Class I Genes; Macaca; Malignant Neoplasms; Mediating; Memory; Modeling; Mus; PD-1 blockade; Participant; Peptides; Persons; Phenotype; Population; Proliferating; Property; Protocols documentation; Role; SIV; Sampling; Stains; T cell differentiation; T cell receptor repertoire sequencing; T cell therapy; T-Lymphocyte; Testing; Time; Tissue Differentiation; Tissue Sample; Tissues; Vaccine Therapy; Viral; Virus; Xenograft procedure; antiretroviral therapy; base; cell killing; chimeric antigen receptor; chimeric antigen receptor T cells; chronic infection; cytotoxic; effector T cell; exhaust; exhaustion; experience; high dimensionality; improved; in vivo; lymph nodes; migration; mouse model; multimodality; overexpression; peripheral blood; programs; response; single-cell RNA sequencing; stem; stem cells; stem-like cell; stemness; transcription factor; viral rebound

PROJECT SUMMARY Nearly 40 million people world-wide are infected with HIV, an infection for which there is no cure. Many strategies that aim to cure HIV focus on harnessing HIV-specific T cells to control the virus that rebounds after antiretroviral therapy (ART) is discontinued because of their ability to specifically recognize and kill HIV-infected cells. However, HIV-specific T cell therapies will not be effective if they cannot overcome the T cell exhaustion that occurs in the setting of chronic antigen stimulation. In mouse models of chronic infection and cancer, T cells enriched for a stem cell memory (TSCM) phenotype or stem-like transcriptional program robustly expand and differentiate into effector cells while resisting exhaustion. We have found that the expression of the stem/memory-promoting transcription factor, TCF-1, is associated with high in vitro proliferative capacity in HIV- specific CD8+ T cells in individuals who naturally control HIV infection and that TCF-1 overexpression leads to better HIV-specific T cell expansion after in vitro peptide stimulation. While T cells that are enriched for stemness programs proliferate and control cancer better in animal models, it is currently unknown whether stem-like T cells (versus, for example, effector-differentiated T cells) are optimal for controlling HIV after ART is stopped. The overarching goal of this proposal is to directly establish the role of T cell stemness in promoting the ability of HIV- specific T cells to expand a functional effector population to control HIV infection after discontinuation of ART. In Aim 1, we will use multi-modal high-dimensional single cell phenotypic and transcriptional profiling to establish whether the proportion of stem-like virus-specific CD8+ T cells on ART correlates with their in vivo expansion and subsequent control of HIV in humans or SIV in macaques after treatment interruption. In Aim 2, we will use envelope (Env)-targeting HIV-specific CAR-T cells with potent anti-HIV activity (duoCAR-T cells) as a model to ask how precisely tuning the level of stemness influences the ability of CAR-T cells to suppress HIV long-term in the HIV Participant-Derived Xenograft (PDX) mouse model. In Aim 3, we will leverage blood and tissue samples from a highly unique clinical trial of people with HIV on ART who receive an infusion of anti-HIV duoCAR- T cells and undergo an ATI. We hypothesize that CAR-T cells that are more stem-like prior to infusion (i.e., either the CAR-T cells in the total pre-infusion product or sub-populations that we identify pre-infusion and then track in vivo post-infusion using single cell paired α/β TCR sequences as “barcodes”) will expand a larger, less- exhausted effector population. These studies will test for the first time in the context of HIV infection the compelling hypothesis that T cells enriched for stemness have greater proliferative capacity and durability and are able to give rise to effector T cells that are better able to control HIV in vivo. We will also comprehensively evaluate other T cell differentiation states that might associate with HIV control after ART discontinuation. Completion of these studies will result in new knowledge about the role of HIV-specific T cell differentiation states in the development of effective T cell-based strategies for HIV cure.

项目摘要 全球近4000万人感染了艾滋病毒，这种感染无法治愈。许多策略 旨在治愈HIV专注于利用HIV特异性T细胞控制抗逆转录病毒后反弹的病毒 治疗（ART）因其特异性识别和杀死感染HIV感染的细胞的能力而停产。 但是，如果HIV特异性的T细胞疗法无法克服T细胞疲劳，将无效 发生在慢性抗原刺激的情况下。在慢性感染和癌症的小鼠模型中，T细胞 丰富用于干细胞记忆（TSCM）表型或类似词干的转录程序的富集 在抵抗疲劳的同时分化为效应细胞。我们发现 茎/记忆促进转录因子TCF-1与HIV的体外增殖能力高有关 自然控制艾滋病毒感染并且TCF-1过表达的个体中的特定CD8+ T细胞导致 体外肽刺激后更好的HIV特异性T细胞扩张。而富含茎的T细胞 程序在动物模型中更加繁殖和控制癌症，目前尚不清楚茎状T细胞是否 （例如，例如，效应子分化的T细胞）是在停止ART后控制HIV的最佳选择。这 该提案的总体目标是直接确定T细胞干的作用在促进HIV的能力中的作用 特定的T细胞以扩大功能效应子群体以控制抗ART后的HIV感染。在 AIM 1，我们将使用多模式的高维单细胞表型和转录分析来建立 茎状病毒特异性CD8+ T细胞在ART上的比例是否与其体内扩张相关 并随后在治疗中断后对人类的艾滋病毒或猕猴中的SIV控制。在AIM 2中，我们将使用 具有潜在抗HIV活性（DuoCar-T细胞）作为靶向HIV特异性CAR-T细胞的靶向HIV特异性CAR-T细胞作为模型 询问确切调整干液水平如何影响CAR-T细胞长期抑制HIV的能力 在HIV参与者衍生的异种移植（PDX）小鼠模型中。在AIM 3中，我们将利用血液和组织 来自艾滋病毒艾滋病患者的高度独特临床试验的样本 T细胞并进行ATI。我们假设在输注之前更具茎状的CAR-T细胞（即 我们识别前输注的总灌注前产物或亚种群中的CAR-T细胞，然后跟踪 使用单细胞配对的α/βTCR序列作为“条形码”）的体内输注后将扩展更大，较少的 - 疲惫的效应子种群。这些研究将在HIV感染的背景下首次检验 令人信服的假设是，富含干茎的T细胞具有更大的增殖能力和耐用性，并且 能够产生能够在体内控制HIV的效应T细胞。我们还将全面 评估其他T细胞分化状态，这些状态可能与ART停用后可能与HIV控制相关联。 这些研究的完成将导致有关HIV特异性T细胞分化状态的作用的新知识 在开发有效的基于T细胞的HIV治疗策略中。