Role of P-TEFB in HIV latency

 描述：隐藏潜伏HIV-1的细胞库排除了现有抗HIV药物治疗感染的可能性。最好描述的潜在储库是长寿命记忆性CD 4 + T细胞。HIV在这些细胞中的潜伏期被认为涉及多种机制：抑制性染色质;细胞基因的转录干扰;细胞转录因子的限制水平，特别是称为P-TEFb的转录延伸因子。我们建议开发选择性上调静息CD 4 + T细胞中P-TEFb的方法，并在体内证明P-TEFb的调节与HIV潜伏期之间的关联。在拟议研究的R21阶段，我们将确定P-TEFb的选择性上调，无论是单独还是与其他潜伏激活剂协同作用，都可以在潜伏期的原代CD 4 + T细胞模型中重新激活潜伏的HIV。在R33阶段的工作中，我们将确定P-TEFb的选择性上调，无论是单独还是与其他药物组合，是否可以重新激活患者样本中的潜伏HIV。为了研究体内P-TEFb和HIV潜伏期，我们将利用免疫组织化学（IHC）和RNA原位杂交（ISH）来检查来自HIV感染个体的淋巴结和脑样品，在抗病毒治疗之前和之后。拟议的工作有可能在体内建立P-TEFb的调节表达与HIV复制和潜伏期之间的关联。重要的是，拟议的工作有可能建立P-TEFb的选择性上调是一种可行的策略，以重新激活体内潜伏的HIV。

 DESCRIPTION: The reservoir of cells harboring latent HIV-1 precludes a cure of infection by existing anti-HIV drugs. The best described latent reservoir is that of long-lived memory CD4+ T cells. Multiple mechanisms are thought to be involved in HIV latency in these cells: repressive chromatin; transcriptional interference by cellular genes; limiting levels of cellular transcriptio factors, especially the transcriptional elongation factor termed P-TEFb. We propose to develop methods to selectively up-regulate P-TEFb in resting CD4+ T cells, as well as to demonstrate associations in vivo between regulation of P-TEFb and HIV latency. In the R21 phase of the proposed research, we will determine if selective up-regulation of P-TEFb, either alone or in synergy with other latency activating agents, can reactivate latent HIV in a primary CD4+ T cells model of latency. In the R33 phase of the work, we will determine if selective up-regulation of P-TEFb, either alone or in combination with other agents, can reactivate latent HIV in patients' samples. To investigate P-TEFb and HIV latency in vivo, we will utilize immunohistochemistry (IHC) and RNA in situ hybridization (ISH) to examine lymph node and brain samples from HIV- infected individuals, both before and after anti-viral therapy. The proposed work has the potential to establish an association in vivo between the regulated expression of P-TEFb and HIV replication and latency. Importantly, the proposed work has the potential to establish that selective up-regulation of P-TEFb is a feasible strategy to reactivate latent HIV in vivo.