Trapping KSHV in its latency: Exploring kinase inhibitors as a class of antivirals that block KSHV lytic reactivation. Homo sapiens

The main objective of the study is to explore the potential of kinase inhibitors in blocking KSHV lytic reactivation. In this study, we identify two kinase inhibitors, AZD5438 and BMS-265246 which block KSHV lytic reactivation by preventing RTA activity at target viral genes. To further understand the mechanisms by which these two compounds inhibit lytic reactivation, we performed RNA seq in TREx-BCBL1-RTA cells treated with each compound and simultaneously induced into lytic cycle with Dox. These samples were also treated with foscarnet to prevent viral DNA polmerase activity (Foscarnet will basically reduce background noise in this case). The study shows that both small molecules perturb KSHV lytic reactivation at multiple levels as listed below:Compounds block expression of downstream KSHV genes (as observed by silenced lytic genes).Compounds antagonize expression of cellular genes that are associated with KSHV lytic reactivation. Cellular genes that would be upregulated during KSHV lytic cycle are downregulated, while cellular genes that would be downregulated during KSHV lytic cycle are upregulated. This disrupted pattern of cellular gene expression denies KSHV of its cellular counterparts that are important for facilitating complete lytic reactivation. For instance, KSHV RTA is the most important viral protein during KSHV lytic reactivation and these drugs reduce expression of important RTA-interacting cellular genes such as FosB, c-Jun and Hey1.