A novel role of hydrogen peroxide in Kaposi sarcoma-associated herpesvirus reactivation

Reactivation of Kaposi sarcoma-associated herpesvirus (KSHV) from latency for lytic replication plays a pivotal role in the development of KS tumors. However, the physiological factors of KSHV reactivation in KS patients remain undefined. Two recent studies independently discovered that the reactive oxygen species (ROS) H(2)O(2) induces KSHV reactivation in latently infected cells, which can be inhibited by H(2)O(2)-specific antioxidants. H(2)O(2) not only directly induces KSHV reactivation but also is involved in spontaneous lytic replication as well as reactivation stimulated by TPA, hypoxia, and cytokines. Furthermore, in a xenograft-based primary effusion lymphoma (PEL) mouse model, in vivo KSHV reactivation is also H(2)O(2)-dependent and can be suppressed by antioxidants. Mechanistically, H(2)O(2) primarily activates the MAPK pathways to induce viral lytic gene expression and replication. This new finding defines a novel role of H(2)O(2) in KS tumorigenesis and highlights great potentials of using antioxidants and anti-inflammatory drugs for the prevention and treatment of KS tumors.