"Chemical-Biology Approach to
Delineate the Mechanism on Action of
HIV-1 Latency Reversing Agents"

Abstract:  Prostratin has been applied as a promising latency reversing agent for the eradication of HIV-1 latent CD4⁺ T cell reservoirs, yet the molecular mechanism of this reactivation remains unclear. Here, we design a novel chemical biology approach revealing that PKC-Mek pathway is essential for prostratin-induced reactivation of latent HIV-1 provirus. First, 7 different Mek inhibitors were identified by the approach that constantly impaired prostratin-induced reactivation. Second, PKC inhibitors, Raf inhibitors, and Erk inhibitors showed different level of inhibition in the latency reversal induced my prostratin. Consistent with this observation, we found that prostratin-induced latency reversal was involved with the kinase activation cascade of PKC-Mek pathway. 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.