title: Reactive oxygen species hydrogen peroxide mediates Kaposi's sarcoma-associated herpesvirus reactivation from latency.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the host following an acute infection. Reactivation from latency contributes to the development of KSHV-induced malignancies, which include Kaposi'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, we show that the reactive oxygen species (ROS) hydrogen peroxide (H₂O₂) induces KSHV reactivation from latency through both autocrine and paracrine signaling. Furthermore, KSHV spontaneous lytic replication, and KSHV reactivation from latency induced by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines are mediated by H₂O₂. Mechanistically, H₂O₂ induction of KSHV reactivation depends on the activation of mitogen-activated protein kinase ERK1/2, JNK, and p38 pathways. Significantly, H₂O₂ scavengers N-acetyl-L-cysteine (NAC), catalase and glutathione inhibit KSHV lytic replication in culture. In a mouse model of KSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication and significantly prolongs the lifespan of the mice. These results directly relate KSHV reactivation to oxidative stress and inflammation, which are physiological hallmarks of KS patients. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs could be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies.
authors.affiliation: Tumor Virology Program, Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Fengchun
authors.initials: F
authors.lastname: Ye
authors.forename: Fuchun
authors.initials: F
authors.lastname: Zhou
authors.forename: Roble G
authors.initials: RG
authors.lastname: Bedolla
authors.forename: Tiffany
authors.initials: T
authors.lastname: Jones
authors.forename: Xiufen
authors.initials: X
authors.lastname: Lei
authors.forename: Tao
authors.initials: T
authors.lastname: Kang
authors.forename: Moraima
authors.initials: M
authors.lastname: Guadalupe
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: Gao
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D005978:Glutathione / Q000378:metabolism; D057809:HEK293 Cells; D006566:Herpesviridae Infections; D019288:Herpesvirus 8, Human / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012514:Sarcoma, Kaposi / Q000821:virology; D015398:Signal Transduction; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002070:Butadienes; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; D017382:Reactive Oxygen Species; C113580:U 0126; D006861:Hydrogen Peroxide; D002374:Catalase; D048031:JNK Mitogen-Activated Protein Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; C093642:SB 203580; D000111:Acetylcysteine