Hepatitis C virus modulates signal peptide peptidase to alter host protein processing

Significance The mechanism by which hepatitis C virus (HCV) evades immune surveillance and causes chronic infection is unclear. We demonstrate here that HCV core protein interferes with the maturation of major histocompatibility complex (MHC) class I catalyzed by signal peptide peptidase (SPP) and induces degradation via HMG-CoA reductase degradation 1 homolog. In addition, we found that the core protein transmembrane domain is homologous to the human cytomegalovirus US2 protein, whose transmembrane region also targets SPP to impair MHC class I molecule expression in a similar manner. Therefore, our data suggest that SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses. Immunoevasins are viral proteins that prevent antigen presentation on major histocompatibility complex (MHC) class I, thus evading host immune recognition. Hepatitis C virus (HCV) evades immune surveillance to induce chronic infection; however, how HCV-infected hepatocytes affect immune cells and evade immune recognition remains unclear. Herein, we demonstrate that HCV core protein functions as an immunoevasin. Its expression interfered with the maturation of MHC class I molecules catalyzed by the signal peptide peptidase (SPP) and induced their degradation via HMG-CoA reductase degradation 1 homolog, thereby impairing antigen presentation to CD8+ T cells. The expression of MHC class I in the livers of HCV core transgenic mice and chronic hepatitis C patients was impaired but was restored in patients achieving sustained virological response. Finally, we show that the human cytomegalovirus US2 protein, possessing a transmembrane region structurally similar to the HCV core protein, targets SPP to impair MHC class I molecule expression. Thus, SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses.