FoxO1 Suppresses Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication and Controls Viral Latency.

Kaposi's sarcoma-associated herpesvirus (KSHV) has latent and lytic replication phases, both of which contribute to the development of KSHV-induced malignancies. Among numerous factors identified to regulate KSHV life cycle, oxidative stress, caused by imbalanced clearing and production of reactive oxygen species (ROS), has been shown to robustly disrupt KSHV latency and induce viral lytic replication. In this study, we identify an important role of antioxidant defense factor forkhead box protein O1 (FoxO1) in KSHV lifecycle. Either chemical inhibition of the FoxO1 function or knockdown of FoxO1 expression led to the increase of intracellular ROS level that was subsequently sufficient to disrupt KSHV latency and induce viral lytic reactivation. On the other hand, treatment with N-acetyl-L-cysteine (NAC), an oxygen free radical scavenger, led to the reduction of FoxO1 inhibition-induced ROS level and ultimately the attenuation of KSHV lytic reactivation. These findings reveal that FoxO1 plays a critical role in keeping KSHV latency in check by maintaining intracellular redox balance.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with several cancers including Kaposi's sarcoma (KS). Both KSHV latent and lytic replication phases are important for the development of KS. Identification of factors regulating KSHV latent to lytic switch can provide insights into the pathogenesis of KSHV-induced malignancies. In this study, we have shown that antioxidant defense factor forkhead box protein O1 (FoxO1) maintains KSHV latency by suppressing viral lytic replication. Inhibition of FoxO1 disrupts KSHV latency and induces viral lytic replication by increasing intracellular ROS level. Significantly, treatment with an oxygen free radical scavenger N-acetyl-L-cysteine (NAC) attenuates FoxO1 inhibition-induced intracellular ROS level and KSHV lytic replication. Our works reveal a critical role of FoxO1 in suppressing KSHV lytic replication, which could be targeted for antiviral therapy.