Chemical-biology approach to delineate the mechanism of action of HIV-1 latency reversing agents

摘要

Prostratin exhibits potent HIV-1 latency reversing activity, yet its molecular mechanism of action has not been defined in detail. Here, we used a novel chemical biology approach which revealed that the protein kinase C-mitogen activated protein kinase kinase (PKC-Mel) pathway is essential for prostratin-induced reactivation of latent HIV-1 provirus. We identified 7 different Mek inhibitors using our approach that constantly impaired prostratin-induced reactivation. We also identified PKC inhibitors, Raf kinase inhibitors, and extracellular signal-regulated kinases (Erk) inhibitors that blocked prostratin-induced reversal of HIV-1 latency. Consistent with these observations, the PKC-Ras-Mek-Erk pathway plays an essential role in the mechanism by which prostratin reactivates latent HIV-1. In addition, we identified several kinase inhibitors that activated HIV-1 latent genes in a significant level individually, including CUDC-101, XMD8-92, PD173074, Quizartinib, and CUDC-907. Therefore, this chemical biology approach provides new methods of revealing the molecular mechanism of LRAs into the HIV-1 eradication research. udThe work represented by this thesis holds public health significances lying mainly in enriching the knowledge of HIV-1 latency reversing agents, contributing to the translational study, and the overall advancement of HIV eradication in public health.