Limiting HIV-1 persistence by targeting stem cell properties of CD4 T cells

通过靶向 CD4 T 细胞的干细胞特性来限制 HIV-1 的持续存在

• 批准号: 8713920
• 负责人: Mathias Lichterfeld
• 金额: $ 26.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-06 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713920
• 关键词: Anti-Retroviral Agents; Antigens; Antineoplastic Agents; Biological Assay; CD4 Positive T Lymphocytes; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; DNA; DNA biosynthesis; Data; Development; Disease remission; Effector Cell; Epithelial; Future; Genes; Goals; HIV-1; Half-Life; Hematologic Neoplasms; Highly Active Antiretroviral Therapy; Human; Human body; Immune; Individual; Infection; Interleukin-17; Intervention; Investigation; Knowledge; Lead; Life; Longevity; Malignant Neoplasms; Memory; Molecular; Molecular Profiling; Natural regeneration; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phylogenetic Analysis; Plasma; Population; Process; Property; Research; Role; Safety; Shapes; Signal Pathway; Signal Transduction; Staging; Stem cells; Structure; Subgroup; T memory cell; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th2 Cells; Therapeutic; Time; Translating; Viral; Virus; Withholding Treatment; Work; antiretroviral therapy; base; beta catenin; cancer stem cell; cytokine; developmental plasticity; in vivo; inhibitor/antagonist; memory CD4 T lymphocyte; precursor cell; programs; public health relevance; research clinical testing; self renewing cell; self-renewal; small molecule; stem; stem cell differentiation; stemness; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): HIV-1 persists despite prolonged periods of maximally suppressive antiretroviral therapy, and rapidly rebounds once treatment is stopped. The development of clinical strategies that reduce HIV-1 persistence and may lead to a long-term drug-free remission of HIV-1 infection represents one of the highest priorities in current HIV-1 research. Such clinical interventions require a detailed knowledge of the cell populations that serve as a long- term reservoir for HIV-1, and can be specifically targeted to reduce viral persistence. Here, we hypothesize that HIV-1 can persist life-long by infecting CD4 T cell populations with stem cell-like properties that can self-renew through homeostatic proliferation and simultaneously repopulate differentiated effector T cell populations. Recent work demonstrates that IL-17-secreting CD4 T cells (Th17) are guided by stem-cell like transcriptional signatures, have extremely long in vivo half-lives and can serve as precursor cell populations for differentiated effector CD4 T cells. In this way, Th17 cells are remarkably similar to T memory stem cells (Tscm), a recently- discovered cell population with a multipotent developmental program that can repopulate all CD4 memory cell subsets, while being maintained by homeostatic self-renewal. To determine whether Th17 and Tscm can serve as a reservoir for viral long-term persistence, we will quantify the amount of HIV-1 DNA and replication- competent virus in these cells, and longitudinally compare viral sequences from these cells to more differentiated T cell subsets and plasma sequences. As a possible strategy to target stem cell-like T cells, we propose to focus on pharmaceutical agents that manipulate wnt/beta-catenin, a phylogenetically-conserved stem cell-specific signaling pathway that maintains the quiescence and multipotency of stem cell-like T cells, and in this way may contribute to long-term HIV-1 persistence. Pharmaceutical targeting of the beta-catenin pathway is currently explored in clinical studies to eliminate cancer stem cells, a small group of long-lived, self- renewing cells with strong oncogenic potential that persist despite classical antineoplastic therapy and in that sense may resemble latently HIV-1 infected stem cell-like T cells that persist despite HAART. Using an existing small molecule inhibitor of the wnt/beta-catenin signaling pathway with an excellent safety/tolerability profile that is currently in phase I clinical trials or eradicating cancer stem cells, we will test whether pharmaceutical targeting of wnt/beta-catenin can be used to induce differentiation of HIV-1 infected T cells with stem cell-like properties and to limit HIV-1 persistence. By defining stem cell-like qualities of immune memory that support HIV-1 persistence, and evaluating possible interventional options to target these, the proposed studies may critically advance the quest for inducing long-term drug-free remissions of HIV-1 infection and lead to translational clinical studies evaluating wnt/beta-catenin inhibitors for reducing HIV-1 persistence in vivo.

描述（由申请人提供）：尽管进行了长时间的最大抑制性抗逆转录病毒治疗，HIV-1 仍持续存在，并且一旦停止治疗就会迅速反弹。开发减少 HIV-1 持久性并可能导致 HIV-1 感染长期无药物缓解的临床策略是当前 HIV-1 研究的最高优先事项之一。此类临床干预措施需要对作为 HIV-1 长期储存库的细胞群有详细的了解，并且可以专门针对减少病毒持续存在。在这里，我们假设 HIV-1 可以通过感染具有干细胞样特性的 CD4 T 细胞群而终生持续存在，这些细胞可以通过稳态增殖进行自我更新，并同时重新填充分化的效应 T 细胞群。最近的研究表明，分泌 IL-17 的 CD4 T 细胞 (Th17) 由干细胞样转录特征引导，具有极长的体内半衰期，并且可以作为分化效应 CD4 T 细胞的前体细胞群。通过这种方式，Th17 细胞与 T 记忆干细胞 (Tscm) 非常相似，Tscm 是最近发现的一种具有多能发育程序的细胞群，可以重新填充所有 CD4 记忆细胞亚群，同时通过稳态自我更新来维持。为了确定 Th17 和 Tscm 是否可以作为病毒长期持续存在的储存库，我们将量化这些细胞中 HIV-1 DNA 和复制能力病毒的数量，并纵向比较来自这些细胞的病毒序列与分化程度更高的 T 细胞亚群和血浆序列。作为靶向干细胞样 T 细胞的一种可能策略，我们建议重点关注操纵 wnt/β-连环蛋白的药剂，这是一种系统发育上保守的干细胞特异性信号通路，可维持干细胞样 T 细胞的静止和多能性，并以这种方式可能有助于 HIV-1 的长期持续存在。目前临床研究中正在探索以 β-连环蛋白途径为靶点的药物靶向消除癌症干细胞，这是一小群具有强致癌潜力的长寿、自我更新细胞，尽管进行了经典抗肿瘤治疗，但仍持续存在，从这个意义上说，可能类似于尽管 HAART 仍持续存在的潜伏 HIV-1 感染的干细胞样 T 细胞。使用现有的Wnt/β-连环蛋白信号通路小分子抑制剂，该抑制剂具有出色的安全性/耐受性，目前正处于I期临床试验或根除癌症干细胞的阶段，我们将测试Wnt/β-连环蛋白的药物靶向是否可用于诱导具有干细胞样特性的HIV-1感染T细胞的分化，并限制HIV-1的持续存在。通过定义支持 HIV-1 持久性的干细胞样免疫记忆质量，并评估针对这些的可能的干预方案，拟议的研究可能会极大地推进诱导 HIV-1 感染长期无药缓解的探索，并导致评估 wnt/β-catenin 抑制剂减少 HIV-1 体内持久性的转化临床研究。