Laboratory of AIDS Research and Immunology, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
Laboratory of Optobiology, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
Virology. 2020 Mar;542:40-53. doi: 10.1016/j.virol.2020.01.006. Epub 2020 Jan 18.
Latent HIV reservoir is a major barrier to absolute HIV cure. Studies on latency reversal agents (LRA) have by far focused mainly on CD4 T-lymphocytes, while myeloid reservoirs remain under-represented despite their persistence and key contribution to HIV pathogenesis. cAMP has been shown to increase HIV-1 transcription in latently-infected monocytes/macrophages. In this communication, we explored the potential of commercially available pharmacological drugs and phosphodiesterase inhibitors to reactivate HIV in latently-infected monocytic cell-line, U1. We showed that increased levels of intracellular cAMP reverse HIV latency in vitro, which is specific to cells of the myeloid lineage. High throughput RNA-seq analysis revealed that cAMP modulates transcriptional profile of latently HIV-infected cells and provides favourable cellular environment for HIV to produce viral proteins. This reactivation of latent HIV was inhibited by Mithramycin A, a selective Sp1 inhibitor, indicating that the reversal of HIV latency in monocytes is driven by transcription factor Sp1.
潜伏的 HIV 储存库是实现 HIV 根治的主要障碍。迄今为止，针对潜伏逆转剂（LRA）的研究主要集中在 CD4 T 淋巴细胞上，而尽管髓样储存库持续存在且对 HIV 发病机制有重要贡献，但它们仍未得到充分重视。环磷酸腺苷（cAMP）已被证明可增加潜伏感染的单核细胞/巨噬细胞中 HIV-1 的转录。在本通讯中，我们探索了市售药理学药物和磷酸二酯酶抑制剂在体外重新激活潜伏感染的单核细胞系 U1 中的 HIV 的潜力。我们表明，细胞内 cAMP 水平的增加可在体外逆转 HIV 潜伏，这是髓系细胞特有的。高通量 RNA-seq 分析显示，cAMP 可调节潜伏 HIV 感染细胞的转录谱，并为 HIV 产生病毒蛋白提供有利的细胞环境。这种潜伏 HIV 的重新激活被米托蒽醌 A 抑制，米托蒽醌 A 是一种选择性 Sp1 抑制剂，表明单核细胞中 HIV 潜伏的逆转是由转录因子 Sp1 驱动的。
