Inhibition of hepatitis E virus replication by zinc-finger antiviral Protein synergizes with IFN-ß.

Hepatitis E virus (HEV) infection is the most common cause of acute viral hepatitis worldwide. However, host-HEV interactions have yet to be fully understood. Zinc-finger antiviral protein (ZAP) is a novel interferon (IFN)-stimulated gene product that inhibits a variety of viruses in synergy with IFN-ß. To evaluate the role of ZAP in HEV infection, its expressions in HEV-infected patients and in cell cultures were measured. We report a significant inhibition of ZAP expression in patients with HEV genotype four acute infection. The expression of ZAP in the HEV life cycle was monitored in cultures of HEV-infected cells. Results indicated that the ZAP level decreased significantly after HEV infection. ZAP over-expression inhibited HEV replication, whereas its knockdown by RNA interference significantly increased HEV RNA. These suggest that ZAP serves as an antiviral in HEV infection. Moreover, silencing ZAP decreased IFN regulatory factor 3 (IRF3) phosphorylation in HEV-infected cells treated with poly(I:C), indicating that ZAP synergizes with IFN-ß. In conclusion, ZAP is an important anti-HEV host factor and in synergy with IFN-ß, inhibits HEV replication.

The different replication between nonenveloped and quasi-enveloped hepatitis E virus.

Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. However, the understanding of the HEV life cycle is limited. In the present study, cells were separately infected with nonenveloped HEV (derived from feces or bile) or quasi-enveloped HEV (derived from the cell culture after serial passages, eHEV) and observed by confocal fluorescence microscopy to investigate the life cycle of HEV. HEV finished its binding and entry into host cells at first 6 h postinoculation (hpi). Cells inoculated with eHEV showed less infectivity than cells inoculated with nonenveloped HEV. Newly synthesized progeny virions were released into the supernatant of cell cultures from 48 hpi. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis results showed that the supernatant's progeny viruses were infectious even after five serial passages. These results show the significant difference between nonenveloped HEV and eHEV, which will provide novel insights into the HEV replication cycle. The efficient cell culture of HEV will promote the development of anti-HEV drugs and vaccines.