Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5'-UTR of <i>TRIM22</i>.

Abstract

Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections. We explored the cellular targets of HBV in response to IFNs using proteome-wide screening. Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, including <i>TRIM22</i>, which is known as an antiretroviral protein. We demonstrated that HBx suppresses the transcription of <i>TRIM22</i> through a single CpG methylation in its 5'-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of <i>TRIM22</i>. We verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system.