Abstract
Hepatitis C virus is major cause of chronic liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Presently available direct-acting antiviral drugs have improved success rate; however, high cost limits their utilization, especially in developing countries like India. In the present study, we evaluated anti-HCV potential of several siRNAs targeted against the HCV RNA-dependent RNA polymerase NS5B and cellular factors, La autoantigen, PSMA7, and human VAMP-associated protein to intercept different steps of viral life cycle. The target genes were downregulated individually as well as in combinations and their impact on viral replication was evaluated. Individual downregulation of La autoantigen, PSMA7, hVAP-A, and NS5B resulted in inhibition of HCV replication by about 67.2%, 50.7%, 39%, and 52%, respectively. However, antiviral effect was more pronounced when multiple genes were downregulated simultaneously. Combinations of siRNAs against La autoantigen with NS5B or hVAP-A resulted in greater inhibition in HCV replication. Our findings indicate that siRNA is a potential therapeutic tool for inhibiting HCV replication and simultaneously targeting multiple viral steps with the combination of siRNAs is more effective than silencing a single target.
Highlights
HCV is an enveloped, single-stranded positive sense, RNA virus belonging to Flaviviridae family that causes acute and chronic hepatitis in humans
We found that siRNA targeted against La autoantigen mRNA reduced its expression by 96.5% in HCV-infected Huh-7.5 cells and HCV replication was reduced by 67.2% (Figures 1(a) and 1(b)) indicating a direct impact of downregulation of La autoantigen on viral replication
Targeting host cell factor is a novel approach for patients who fail to respond to current direct antiviral agents (DAA) treatment or develop drug resistance
Summary
HCV is an enveloped, single-stranded positive sense, RNA virus belonging to Flaviviridae family that causes acute and chronic hepatitis in humans. Few recent reports showed that combinations of siRNAs targeted against different cellular or viral factors have synergistic anti-HCV effects [32,33,34,35,36]. Most of these studies were restricted to either viral entry or the viral genome. Gene specific siRNAs were designed against cellular factors, La autoantigen, PSMA7, hVAP-A, and viral factor HCV NS5B and screened for HCV inhibition individually as well as in combinations. Downregulation of viral replications was assessed by semiquantitative RT-PCR, western blotting, and immunostaining
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