Preventing CD4+ T memory cells from becoming HIV reservoirs

摘要 治愈艾滋病毒/艾滋病需要清除潜伏的、转录沉默的前病毒库的策略， 即使在有效的高效抗逆转录病毒治疗的情况下，HIV仍然存在于CD 4 + T记忆细胞中。 尽管进行了深入的研究，但我们对艾滋病毒的种子和维持的分子机制的理解 原代人CD 4+记忆T细胞中的储存库仍然不完整。 我们的初步数据表明，白细胞介素-15（IL-15），唯一的γ细胞因子在急性期上调， HIV感染，通过限制失活增加人CD 4 + T记忆细胞对感染的易感性 因子SAMHD 1。此外，IL-15特异性地增加具有干细胞样T细胞的CD 4 + T记忆细胞的数量。 在HIV感染的CD 4 + T细胞群体中的TSCM特性。我们假设HIV感染的CD 4 + T记忆 具有干细胞样特性的细胞（CD 4 + T中央记忆/干细胞样）启动并维持持续的 控制病毒复制的患者中的病毒储库。我们将探索控制 感染易感性和潜伏期的维持， 例如飞行时间质谱（CyTOF）、基因组编辑和下一代测序。我们将 识别CD 4 + T记忆细胞中的流产、沉默和生产性感染， 并调节这些途径，使CD 4 + T记忆细胞对感染难治。我们 将研究FDA批准的JAK 1/2和mTOR抑制剂如何调节CD 4 + T细胞的感染和增殖 记忆细胞我们将通过产生分层的细胞谱系来定义负责体内HIV持久性的细胞谱系。 在相同的遗传位置插入但从不同的CD 4 + T细胞获得的患者源性前病毒图谱 使用高分辨率的下一代测序方法的记忆群体。 拟议的研究不仅将表征建立和维持HIV免疫的CD 4 + T记忆细胞， 水库，但也检查是否FDA批准的治疗干预措施，可用于防止潜在的 HIV感染和/或消除HIV在人CD 4 + T记忆细胞区室中的持续存在。

ABSTRACT Curing HIV/AIDS requires strategies to purge reservoirs harboring latent, transcriptionally silent proviruses, as HIV persists in CD4+ T memory cells even in the presence of effective highly active antiretroviral therapy. Despite intensive research, our understanding of the molecular mechanisms that seed and maintain the HIV reservoir in primary human CD4+ memory T cells remains incomplete. Our preliminary data indicate that interleukin-15 (IL-15), the only gamma cytokine up-regulated during acute HIV infection, increases human CD4+ T memory cell susceptibility to infection by inactivation of the restriction factor SAMHD1. Further, IL-15 specifically increases the number of CD4+ T memory cells with stem cell like properties (TSCM) in HIV-infected CD4+ T cell populations. We hypothesize that HIV infected CD4+ T memory cells with stem cell-like properties (CD4+ T central memory/stem cell-like) initiate and maintain the persistent viral reservoir in patients with controlled viral replication. We will probe the molecular mechanisms controlling infection susceptibility and latency maintenance in primary human CD4+ T cells using established techniques, such as mass-cytometry by time of Flight (CyTOF), genome editing and next generation sequencing. We will identify abortive, silent and productive infections in CD4+ T memory cells, define the cellular programs specific for HIV persistence and modulate these pathways to render CD4+ T memory cells refractory to infection. We will examine how FDA approved JAK1/2 and mTOR inhibitors modulate infection and proliferation of CD4+ T memory cells. We will define cell lineages responsible for HIV persistence in vivo by generating hierarchical maps of patient-derived proviruses inserted at the same genetic location but obtained from distinct CD4+ T memory populations using high-resolution, next generation sequencing approaches. The proposed studies will not only characterize the CD4+ T memory cells that establish and maintain the HIV reservoir, but also examine whether FDA approved therapeutic interventions may be used to prevent latent HIV infection and/or eliminate HIV persistence in the human CD4+ T memory cell compartment.