Targeting HIV persistence in CD4+ T memory stem cells

 描述（由申请人提供）：消除艾滋病毒持续存在是治愈艾滋病毒/艾滋病的必要步骤。事实上，由于目前的抗病毒药物无法从艾滋病毒感染者体内清除病毒，因此需要终身的高效抗逆转录病毒治疗。尽管进行了深入的研究，但仍没有有效的策略来消除来自HIV感染患者的潜伏的、转录沉默的HIV前病毒，这些患者具有良好的HIV感染控制。新出现的证据表明，CD 4 + T记忆干细胞（TSCM），所有CD 4 + T细胞记忆群体中分化程度最低的，支持HIV感染。然而，在我们关于具有干细胞样特性的CD 4 + T细胞（TSMC）对建立HIV潜伏期和持久性的影响的机制和程度的知识中仍然存在根本性的差距。我们的初步数据表明，TSCM从根本上不同于其他CD 4 + T记忆细胞。由于干细胞可以长时间更新和产生子代细胞，我们假设感染的TSCM持续存在，维持和种子携带潜伏前病毒的CD 4 T细胞。我们将使用质谱、3D-FISH、蛋白质组学和基因组学来探索原代人CD 4 T干细胞特异性潜伏期建立和维持的分子机制。我们将定义流产，沉默和生产性感染的相关性在CD 4 + TSCM，定义细胞程序的艾滋病毒持久性特异性在CD 4 + TSCM和探测的CD 4 + TSCM水库在艾滋病毒阳性患者自发或HAART辅助控制艾滋病毒感染。我们将测试在多大程度上少量的整合可以种子水库携带相同的潜伏前病毒在多个细胞代。了解潜在的潜伏期建立和维持在CD 4 + TSCM的分子机制是至关重要的，以制定有针对性的干预措施，旨在缩小和清除艾滋病毒在CD 4 + TSCM的持久性。

 DESCRIPTION (provided by applicant): Eliminating HIV persistence is an obligated step to curing HIV/AIDS disease. Indeed, life-long highly active antiretroviral therapy is required since current antiviral drugs fail to eliminate the virus from HIV-infected patients. Despite intensive research there are no effective strategies to eliminate latent, transcriptionally silent HIV proviruses from HIV infected patients with well-controlled HIV infection. Emerging evidence suggest that CD4+ T memory stem cells (TSCM), the least differentiated of all CD4+ T cell memory populations, support HIV infection. There remains, however, a fundamental gap in our knowledge regarding the mechanisms and the extent of the impact of CD4+ T cells with stem like properties (TSMC) on establishment of HIV latency and persistence. Our preliminary data suggests that TSCM are fundamentally different from other CD4+ T memory cells. Since stem cells can renew and generate progeny cells for prolonged periods, we hypothesize that infected TSCM persist, maintain and seed CD4 T cells carrying latent proviruses. We will use mass-cytometry, 3D-FISH, proteomics and genomics to probe for the molecular mechanisms of latency establishment and maintenance specific for primary human CD4 T stem cells. We will define correlates of abortive, silent and productive infections in CD4+ TSCM, define the cellular programs specific for HIV persistence in CD4+ TSCM and probe for the CD4+ TSCM reservoir in HIV positive patients with spontaneous or HAART-assisted control of HIV infection. We will test to what extent a small number of integrations can seed the reservoir carrying the same latent provirus over multiple cell generations. Understanding the molecular mechanisms underlying latency establishment and maintenance in CD4+ TSCM is essential to develop targeted interventions aimed at shrinking and purging HIV persistence in CD4+ TSCM.