ADAR1 Facilitates KSHV Lytic Reactivation by Modulating the RLR-Dependent Signaling Pathway

Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus that exhibits two alternative life cycles: latency and lytic reactivation. During lytic reactivation, host innate immune responses are activated to restrict viral replication. Here, we report that adenosine deaminase acting on RNA 1 (ADAR1) is required for optimal KSHV lytic reactivation from latency. Knockdown of ADAR1 in KSHV latently infected cells inhibits viral gene transcription and viral replication during KSHV lytic reactivation. ADAR1 deficiency also significantly increases type I interferon production during KSHV reactivation. This increased interferon response is dependent on activation of the RIG-I-like receptor (RLR) pathway. Depletion of ADAR1 together with either RIG-I, MDA5, or MAVS reverses the increased IFNβ production and rescues KSHV lytic replication. These data suggest that ADAR1 serves as a proviral factor for KSHV lytic reactivation and facilitates DNA virus reactivation by dampening the RLR pathway-mediated innate immune response.