Targeting HIV persistence in CD4+ T memory stem cells

 描述(由申请人提供)：消除艾滋病毒持久性是治愈艾滋病毒/艾滋病的义务步骤。事实上，由于目前的抗病毒药物无法从艾滋病毒感染患者身上消除病毒，因此需要终身高效的抗逆转录病毒治疗。尽管进行了密集的研究，但没有有效的战略来消除艾滋病毒感染患者中潜伏的、转录沉默的艾滋病毒前病毒，这些患者的艾滋病毒感染得到了良好的控制。新出现的证据表明，CD4T记忆干细胞(TSCM)是所有CD4T细胞记忆群体中分化最小的，支持HIV感染。然而，关于具有干细胞样特性的CD4T细胞(TSMC)对HIV潜伏期和持久性建立的影响的机制和程度，我们的认识仍然存在根本差距。我们的初步数据表明，TSCM与其他CD4T记忆细胞有根本的不同。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、维持和播种携带潜伏期前病毒的CD4T细胞。我们将使用质量细胞术、3D-FISH、蛋白质组学和基因组学来探索人类原代CD4T干细胞特有的潜伏期建立和维持的分子机制。我们将定义CD4 TSCM中流产、静止性和生产性感染的相关性，定义CD4 TSCM中专用于HIV持久性的细胞程序，并探索在自发或HAART辅助控制HIV感染的HIV阳性患者中的CD4 TSCM储存库。我们将测试少量的整合在多大程度上可以在多个细胞世代中培育携带相同潜伏前病毒的储存库。了解CD4TSCM潜伏期建立和维持的分子机制对于开发旨在缩小和清除CD4TSCM中HIV持久性的有针对性的干预措施是至关重要的。

 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.