Preventing CD4+ T memory cells from becoming HIV reservoirs

摘要 治疗艾滋病毒/艾滋病需要清除潜伏的、转录上沉默的前病毒的宿主，如 即使在有效、高效的抗逆转录病毒治疗存在的情况下，HIV仍然存在于CD4+T记忆细胞中。 尽管进行了大量研究，但我们对传播和维持艾滋病毒的分子机制的理解 人类原代CD4+记忆T细胞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)，唯一的伽玛细胞因子，在急性加重期上调 HIV感染，通过限制失活增加人类CD4+T记忆细胞对感染的敏感性 因子SAMHD1。此外，IL-15特异性地增加具有干细胞样细胞的CD4+T记忆细胞的数量 HIV感染的CD4+T细胞群体的特性(TSCM)。我们假设HIV感染了CD4+T细胞记忆 具有干细胞样属性(CD4+T中心记忆/干细胞样细胞)的细胞启动和维持持久的 控制病毒复制的患者中的病毒库。我们将探索控制的分子机制 利用已建立的技术在原代人类CD4+T细胞中的感染敏感性和潜伏期维持， 例如飞行时间质量细胞术(CyTOF)、基因组编辑和下一代测序。我们会 识别CD4+T记忆细胞中的流产、静止性和生产性感染，定义特定的细胞程序 对于HIV的持久性，并调节这些途径，使CD4+T记忆细胞对感染难以抵抗。我们 将研究FDA批准的JAK1/2和mTOR抑制剂如何调节CD4+T细胞的感染和增殖 存储单元。我们将通过生成分层结构来定义体内HIV持续存在的细胞谱系 插入在相同遗传位置但来自不同的CD4+T细胞的患者来源的前病毒的图谱 使用高分辨率、下一代测序方法的存储器种群。 拟议中的研究不仅将描述建立和维持HIV病毒的CD4+T记忆细胞的特征 但也要检查FDA批准的治疗干预措施是否可以用于预防潜伏期 HIV感染和/或消除HIV在人类CD4+T记忆细胞室中的持久性。

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.