Hydrogen Peroxide Induce Human Cytomegalovirus Replication through the Activation of p38-MAPK Signaling Pathway

Human cytomegalovirus (HCMV) is a major risk factor in transplantation and AIDS patients, which induces high morbidity and mortality. These patients infected with HCMV experience an imbalance of redox homeostasis that cause accumulation of reactive oxygen species (ROS) at the cellular level. H(2)O(2), the most common reactive oxygen species, is the main byproduct of oxidative metabolism. However, the function of H(2)O(2) on HCMV infection is not yet fully understood and the effect and mechanism of N-acetylcysteine (NAC) on H(2)O(2)-stimulated HCMV replication is unclear. We, therefore, examined the effect of NAC on H(2)O(2)-induced HCMV production in human foreskin fibroblast cells. In the present study, we found that H(2)O(2) enhanced HCMV lytic replication through promoting major immediate early (MIE) promoter activity and immediate early (IE) gene transcription. Conversely, NAC inhibited H(2)O(2)-upregulated viral IE gene expression and viral replication. The suppressive effect of NAC on CMV in an acute CMV-infected mouse model also showed a relationship between antioxidants and viral lytic replication. Intriguingly, the enhancement of HCMV replication via supplementation with H(2)O(2) was accompanied with the activation of the p38 mitogen-activated protein kinase pathway. Similar to NAC, the p38 inhibitor SB203580 inhibited H(2)O(2)-induced p38 phosphorylation and HCMV upregulation, while upregulation of inducible ROS was unaffected. These results directly relate HCMV replication to H(2)O(2), suggesting that treatment with antioxidants may be an attractive preventive and therapeutic strategy for HCMV.