CpG‐containing immunostimulatory sequences (ISS) exhibit potent inhibition of HCV replication in HCV replicon line

Abstract

Only 50% of HCV‐infected patients respond to current treatment and many subjects experience adverse effects stemming from systemic IFN‐a administration, underlining the need for safer and more efficacious therapies. Exposure of Huh‐7 replicon cells, an in vitro HCV replication system, to supernatants from human PDCs stimulated with IFN‐a‐inducing CpG‐C ISS also displayed a potent ability to inhibit HCV replication that correlated with the quantity of IFN‐a present in the supernatants. To more closely mimic the in vivo situation, co‐cultures of replicon cells and human PDCs were established. In this case, HCV replication was also inhibited by direct ISS treatment, and optimal inhibition was achieved using lower doses of ISS than were necessary via PDC‐supernatant transfer. Type I IFN blockade during the co‐culture was insufficient to completely inhibit HCV replication, suggesting that other ISS‐induced factors contribute to controlling HCV replication. Furthermore, the dose of efficacious ISS could be further reduced when administered together with the antiviral drug ribavirin, suggesting that effective combination therapy might be achieved with low doses of ISS. These results suggest that a novel combination therapy of ISS and ribavirin could exhibit potent HCV suppressive activity while avoiding adverse events associated with high levels of systemic IFN‐a.