Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA.
Curr Opin HIV AIDS. 2011 Jan;6(1):4-11. doi: 10.1097/COH.0b013e328340ffbb.
Despite the remarkable success of intensive antiretroviral drug therapy in blocking the HIV replication, the virus persists in a small number of cells in which HIV has been transcriptionally silenced. This review will focus on recent insights into the HIV transcriptional control mechanisms that provide the biochemical basis for understanding latency.
Latency arises when the regulatory feedback mechanism driven by HIV Tat expression is disrupted. Small changes in transcriptional initiation, induced by epigenetic silencing, can lead to restrictions in Tat levels and entry of proviruses into latency. In resting memory T-cells, which carry the bulk of the latent viral pool, additional restrictions limiting cellular levels of the essential Tat cofactor P-TEFb and the transcription initiation factors nuclear factor kappa B and nuclear factor of activated T cells ensure that the provirus remains silenced unless the host cell is activated.
Strategies to purge the latent proviral pool require nontoxic activator molecules. The multiple restrictions imposed on latent proviruses that need to be overcome suggest that proviral reactivation will not be achieved when only a single reactivation step is targeted but will require both removal of epigenetic blocks and the activation of P-TEFb. Alternatively, new inhibitors that block proviral reactivation could be developed.
尽管强化抗逆转录病毒药物治疗在阻止 HIV 复制方面取得了显著成功，但病毒仍存在于少数转录沉默的细胞中。本文将重点介绍 HIV 转录控制机制的最新研究进展，这些机制为理解潜伏期提供了生化基础。
当 HIV Tat 表达驱动的调节反馈机制被破坏时，潜伏期就会出现。转录起始的微小变化，由表观遗传沉默诱导，可导致 Tat 水平受限，并使前病毒进入潜伏期。在携带大部分潜伏病毒池的静止记忆 T 细胞中，额外的限制限制了必需的 Tat 辅助因子 P-TEFb 和转录起始因子核因子 kappa B 和激活 T 细胞核因子的细胞水平，从而确保前病毒保持沉默，除非宿主细胞被激活。
清除潜伏性前病毒池的策略需要非毒性激活分子。潜伏性前病毒所受到的多重限制需要克服，这表明仅针对单个激活步骤将无法实现前病毒的重新激活，而需要去除表观遗传阻断并激活 P-TEFb。或者，可以开发新的抑制物来阻断前病毒的重新激活。
