The Effects Of Host Factors On Hepatitis C Virus Replication

With an estimated 71 million people infected worldwide according to the report from World Health Organization,hepatitis C virus(HCV)is a considerable threat to global health.Among those with acute HCV infection,80% develop a persistent infection with a high risk of causing chronic hepatitis,cirrhosis,and hepatocellular carcinoma.With the continuous development of research,new progress has been made in the study of drugs for the treatment of HCV infection.A direct antiviral drug-sofosbuvir has become the first oral treatment for HCV-infected patients in 2013.It has achieved good curative effect compared with traditional PEG-IFN and ribavirin combination therapy.Although HCV-infected patients are now treated with direct-acting antiviral therapy,these patients still face several hurdles,such as high treatment costs,strong pathogenicity of multiple HCV genotypes and drug-resistant variants.Also,there is no preventive HCV vaccine.HCV life cycle in host cells is extremely complex which includes entry,translation,replication,and the assembly and release of virons.Because HCV infection is tightly associated with viral and host proteins,an alternative strategy to combat HCV is targeting host proteins.EPSTI1(epithelial stromal interaction 1),as an IFN-stimulated gene,plays an important role in cell apoptosis,breast cancer development,and immune response.In the present study,we found that HCV infection upregulated EPSTI1 mRNA and protein levels,which were positively correlated with viral titers.Also,we found that all of three types of interferons(type I,type II,and type III)induced the transcription and expression of EPSTI1.At the same time,exogenous overexpression of EPSTI1 in hepatoma cell line decreased HCV RNA and Core protein levels,while knockdown of endogenous EPSTI1 increased HCV RNA and Core protein levels.It was found that EPSTI1 did not affect the entry of HCV and the assembly and release process of virions,but inhibited HCV subgenomic replication.It is speculated that EPSTI1 may play a role in the replication process of HCV.SPSB2(SPRY domain-and SOCS box-containing protein 2)belongs to SPSB family,and it recruits target proteins by the SPRY domain and forms E3 ubiquitin ligase ECS(Elongin BC-Cullin5-SOCS box)complex by the SOCS box.As an adaptor protein,it can regulate the host's response to infection.In the present study,we found that HCV infection significantly upregulated the mRNA and protein levels of SPSB2 in HCVcc-infected cells.Overexpression of SPSB2 in hepatoma cells decreased HCV RNA and protein levels,while knockdown of endogenous SPSB2 increased HCV RNA and protein levels.And also the inhibitory effect of SPSB2 on HCV replication depended on its SOCS box.Additionally,we demonstrated that SPSB2 interacted with HCV structural protein E1 and nonstructural protein protein 5A(NS5A)via the C-terminal portion of the SPSB2 SPRY domain.Furthermore,SPSB2 induced NS5 A ubiquitination and mediated NS5 A degradation.Collectively,host factor SPSB2 significantly inhibited HCV replication by interacting and degrading NS5 A.ASB9(ankyrin repeat and SOCS box containing 9),a member of ASB family,binds to the CK kinases CKB and uMtCK via the ANK repeats and participates in the E3 ubiquitin ligase ECS complex through the C-terminal SOCS box,and then degrades CKB and uMtCK by the proteasome pathway.Also,ASB9 is a tumor suppressor which is an important indicator for the clinical diagnosis of breast cancer and colon cancer.In the present study,it was found that ASB9 interacted with HCV non-structural protein NS5 A via its first ANK repeat.Overexpression of ASB9 in hepatoma cells inhibited HCV replication,whereas knockdown of endogenous ASB9 increased HCV replication.And also the inhibitory effect of ASB9 on HCV replication depended on its SOCS box.