Specific activation of HIV-1 from monocytic reservoir cells by bromodomain inhibitor in humanized mice in vivo
The combination antiretroviral therapy (cART) effectively suppresses HIV-1 infection and enables HIV-infected individuals to live long productive lives. However, the persistence of HIV-1 reservoir cells with latent or low-replicating HIV-1 in patients under cART make HIV-1 infection an incurable disease. Recent studies have focused on the development of strategies such as epigenetic modulators to activate and purge these reservoirs. Bromodomain inhibitors (BETi) are epigenetic modulating compounds able to activate viral transcription in HIV-1 latency cell lines in a positive transcription elongation factor b (P-TEFb)-dependent manner. Little is known about the efficacy of activating HIV-1 reservoir cells under cART by BETi in vivo. In this study, we seek to test the potential of a BETi (I-BET151) in activating HIV-1 reservoir cells under effective cART in humanized mice in vivo. We discover that I-BET151 efficiently activates HIV-1 transcription in monocytic cells, but not in CD4+ T cells, during suppressive cART in vivo. We further reveal that HIV-1 proviruses in monocytic cells are more sensitive to I-BET151 treatment than in T cells in vitro. Finally, we demonstrate that I-BET151-activated viral transcription in monocytic cells is dependent on both CDK2 and CDK9, whereas only CDK9 is involved in activation of HIV-1 by I-BET151 in T cells. Our findings indicate a role of myeloid cells in HIV-1 persistence, and highlights the limitation of measuring or targeting T cell reservoirs alone in terms of HIV-1 cure, as well as provides a potential strategy to reactivate monocytic reservoirs during cART.\n\nIMPORTANCEIt has been reported the low level of active P-TEFb critically contributes to the maintenance of HIV-1 latency or low-replication in HIV-1 reservoir cells under cART. Bromodomain inhibitors are used to activate HIV-1 replication in vitro but their effect on activation of the HIV-1 resevoirs with cART in vivo is not clear. We found that BETi (I-BET151) treatment reactivated HIV-1 gene expression in humanized mice during suppressive cART. Interestingly, I-BET151 preferentially reactivated HIV-1 gene expression in monocytic cells, but not in CD4 T cells. Furthermore, I-BET151 significantly increased HIV-1 transcription in monocytic cells, but not in latently infected CD4 T cells, via CDK2-dependent mechanisms. Our findings suggest that BETi can preferentially activate monocytic HIV-1 reservoir cells, and a combination of latency reversal agents targeting different cell types and pathways is needed to achieve reactivation of different HIV-1 reservoir cells during cART.