Fine-Tuning of the Kaposi’s Sarcoma-Associated Herpesvirus Life Cycle in Neighboring Cells through the RTA-JAG1-Notch Pathway

Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is an oncogenic pathogen that displays latent and lytic life cycles. In KS lesions, infiltrated immune cells, secreted viral and/or cellular cytokines, and hypoxia orchestrate a chronic pro-lytic microenvironment that can promote KSHV reactivation. However, only a small subset of viruses spontaneously undergoes lytic replication in this pro-lytic microenvironment while the majority remains in latency. Here, we show that the expression of the Notch ligand JAG1 is induced by KSHV-encoded replication and transcription activator (RTA) during reactivation. JAG1 up-regulation activates Notch signaling in neighboring cells and prevents viral lytic replication. The suppression of JAG1 and Notch1 with inhibitors or small interfering RNA promotes lytic replication in the presence of RTA induction or under conditions of hypoxia. The underlying mechanism involves the Notch downstream effector hairy and enhancer of split 1 (Hes1), which directly binds lytic gene promoters and attenuates viral lytic gene expression. RTA interacts with lymphoid enhancer-binding factor 1 (LEF1), disrupts LEF1/Groucho/TLE suppressive complexes and releases LEF1 to activate JAG1 expression. Taken together, our results suggest that cells with viral lytic replication can inhibit KSHV reactivation in neighboring cells through an RTA-JAG1-Notch pathway. These data provide insight into the mechanism by which the virus maintains the balance between lytic and latent infection in the pro-lytic tumor microenvironment.