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Genomic Analysis of anti-HBV Activity by siRNA and Lamivudine in Stable HBV-producing Cell

ABSTRACT: We designed seven siRNAs based on the conserved HBV sequences and tested their effects on the expression of HBV genes following sorting of siRNA positive cells. Among these seven siRNAs, siRNA-1 and siRNA-7 were found to effectively suppress HBV gene expressions. We further addressed the global gene expression changes in stable HBV-producing cells induced by siRNA-1 and siRNA-7 using human genome-wide oligo microarrays. Data from the gene expression profilings indicated that siRNA-1 and siRNA-7 altered the expression of 54 and 499 genes, respectively, in HepG2.2.15 cells, which revealed the different siRNA had a varied pattern of gene expression profile and suggested complicated influence of siRNA on host cell. We further observed that eighteen of these genes were suppressed by both siRNA-1 and siRNA-7. Interestingly, seven of these genes were originally activated by HBV, which suggested these seven genes might be involved in the HBV-host cell interaction. Finally, we have compared the effects of siRNA and lamivudine on HBV and host cell, which revealed that siRNA is more effective in inhibiting the HBV expression at mRNA and protein level in vitro, and the gene expression profiling of HepG2.2.15 treated by lamivudine is totally different from siRNA¡¯s. Keywords: other

ORGANISM(S): Homo sapiens

PROVIDER: GSE3049 | GEO | 2005/10/01

SECONDARY ACCESSION(S): PRJNA93069

REPOSITORIES: GEO

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Project description:Hepatitis B virus (HBV) causes both acute and chronic liver inflammation. Approximately 600,000 CHB patients each year die of HBV-related diseases such as cirrhosis and liver cancer. Therefore, CHB remains a global health concern. Although there have been anti-HBV agents for treating CHB, they have some limitations including viral-drug resistance and adverse effects. Type III IFN or IFN-λ is promising to use as anti-HBV agents because of its anti-viral activities like type I IFNs. In addition, the expression of its receptor, IFNLR1, is limited only in epithelial cells including hepatocytes. Thus, treatment with IFN-lambda results in less side effects compared to IFN-alpha treatment. IFN-lambdas have been shown to inhibit the replication of several viruses including IAV, DENV, EMCV, HIV, HCV, and HBV; however, there have been no studies on the effects of IFN-λ3, the highest activity among other subtypes, on HBV replication. Therefore, this study aims to determine antiviral activities of IFN-λ3 against HBV replication and to investigate its molecular mechanism responsible for suppressing HBV propagation. The results showed that HBV transcripts and amount of intracellular HBV DNA were decreased in HepG2.2.15 cells, stable HBV-transfected hepatoblastoma cell line, treated with IFN-λ3 in a dose-dependent manner. This indicated that IFN-λ3 could inhibit HBV replication. Next, we performed quantitative proteomics to investigate the proteome changes in HepG2.2.15 treated with IFN-λ3. The proteins that changed their expressions were involved in several biological processes such as defense to viral infection, immune responses, cell-cell adhesion, transcription, translation, and metabolism. We further confirmed the proteomics results by immunoblotting assay. Consistent with MS data, it found that the expression of OAS3, SAMHD1 and STAT1 were increased as a result of IFN-λ3 stimulation. These results indicated that proteomics results were reproducible and reliable. Finally, we proposed 3 possible mechanisms involved in suppressing HBV replication including i.) IFN-λ3 induced anti-viral proteins affecting many steps in HBV life cycle ii.) IFN-λ3 promoted antigen processing and antigen presentation and iii.) IFN-λ3 rescued RIG-I signaling to promote both type I and type III IFN production.

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Genomic Analysis of anti-HBV Activity by siRNA and Lamivudine in Stable HBV-producing Cell

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