Mpox virus OPG175 negatively regulates viral replication by controlling Wnt signaling

Mpox virus (MPXV) infection exhibits different case fatality rates and symptoms depending on its clade. However, there has been insufficient molecular biological analysis of the differences between clades. Here, we investigated whether clades can be distinguished by focusing on the expression of <i>MPXV</i> genes. The replication efficiency of MPXV clade IIb, responsible for the 2022 mpox outbreak, was lower than that of clades Ia and IIa. We found that OPG175 was highly expressed in MPXV clade IIb-infected cells. Suppression of OPG175 expression significantly increased the infectious titer of MPXV, whereas OPG175 overexpression significantly decreased it. We also found that OPG175 overexpression enhanced the expression of Wnt signaling-related genes, and activation of Wnt signaling decreased MPXV replication efficiency. Therefore, high OPG175 expression in MPXV clade IIb-infected cells likely inhibits MPXV replication via activation of Wnt signaling.