Reactive oxygen species hydrogen peroxide mediates Kaposi's sarcoma-associated herpesvirus reactivation from latency

Kaposi''s sarcoma-associated herpesvirus (KSHV) establishes a latentinfection in the host following an acute infection. Reactivation from latencycontributes to the development of KSHV-induced malignancies, which includeKaposi''s sarcoma (KS), the most common cancer in untreated AIDS patients,primary effusion lymphoma and multicentric Castleman''s disease. However,the physiological cues that trigger KSHV reactivation remain unclear. Here, weshow that the reactive oxygen species (ROS) hydrogen peroxide(H₂O₂) induces KSHV reactivation from latency throughboth autocrine and paracrine signaling. Furthermore, KSHV spontaneous lyticreplication, and KSHV reactivation from latency induced by oxidative stress,hypoxia, and proinflammatory and proangiogenic cytokines are mediated byH₂O₂. Mechanistically, H₂O₂induction of KSHV reactivation depends on the activation of mitogen-activatedprotein kinase ERK1/2, JNK, and p38 pathways. Significantly,H₂O₂ scavengers N-acetyl-L-cysteine (NAC), catalaseand glutathione inhibit KSHV lytic replication in culture. In a mouse model ofKSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication andsignificantly prolongs the lifespan of the mice. These results directly relateKSHV reactivation to oxidative stress and inflammation, which are physiologicalhallmarks of KS patients. The discovery of this novel mechanism of KSHVreactivation indicates that antioxidants and anti-inflammation drugs could bepromising preventive and therapeutic agents for effectively targeting KSHVreplication and KSHV-related malignancies.