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

描述(申请人提供)：HIV-1病毒尽管经过了长时间的最大限度抑制抗逆转录病毒治疗，但仍然存在，一旦治疗停止，艾滋病毒-1病毒会迅速反弹。开发减少HIV-1持久性并可能导致HIV-1感染的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。这样的临床干预需要详细了解作为HIV-1长期储存库的细胞群体，并可以有针对性地减少病毒的持久性。在这里，我们假设HIV-1可以通过感染具有干细胞样特性的CD4T细胞群而持续终生，这些干细胞样特性可以通过稳态增殖自我更新，同时重新填充分化的效应器T细胞群。最近的工作表明，分泌IL-17的CD4T细胞(Th17)受干细胞样转录信号的引导，在体内具有极长的半衰期，可以作为分化效应CD4T细胞的前体细胞群。在这种情况下，Th17细胞与T记忆干细胞(Tscm)非常相似，T记忆干细胞是最近发现的一种细胞群体，具有多潜能的发育程序，可以重新填充所有的CD4记忆细胞亚群，同时通过自身平衡的自我更新来维持。为了确定Th17和Tscm是否可以作为病毒长期存在的储存库，我们将量化这些细胞中HIV-1 DNA和复制能力病毒的数量，并纵向比较这些细胞中的病毒序列与更分化的T细胞亚群和血浆序列。作为一种可能的针对干细胞样T细胞的策略，我们建议将重点放在操纵WNT/β-连环蛋白的药物上，WNT/β-连环蛋白是一种在系统发育上保守的干细胞特异性信号通路，它维持干细胞样T细胞的静止和多能性，从而可能有助于HIV-1的长期存在。目前，针对β-连环蛋白途径的药物靶向正在临床研究中进行探索，以消除癌症干细胞。癌症干细胞是一小群长寿命、自我更新的细胞，具有很强的致癌潜力，尽管进行了经典的抗肿瘤治疗，但它们仍然存在，从这个意义上说，它可能类似于潜伏感染HIV-1的干细胞样T细胞，尽管进行了HAART，但它们仍然存在。利用一种现有的WNT/β-连环蛋白信号通路小分子抑制剂，该小分子抑制剂具有良好的安全性/耐受性，目前正处于I期临床试验或根除癌症干细胞，我们将测试针对WNT/β-连环蛋白的药物靶向是否可以用于诱导感染HIV-1的具有干细胞样特性的T细胞分化，并限制HIV-1的持久性。通过定义支持HIV-1持久性的干细胞样免疫记忆特性，并评估针对这些特性的可能干预选择，拟议的研究可能关键地推进诱导HIV-1感染的长期无药物缓解的探索，并导致评估WNT/β-Catenin抑制剂在体内降低HIV-1持久性的转译临床研究。

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.