Synergistic antiviral effect of a combination of mouse interferon‐α and interferon‐γ on mouse hepatitis virus

Fuchizaki, Uichiro; Kaneko, Shuichi; Nakamoto, Yasunari; Sugiyama, Yoshihiro; Imagawa, Kenichi; Kikuchi, Mikio; Kobayashi, Kenichi

Although interferon (IFN)‐α and IFN‐γ have been reported to exhibit a synergistic antiviral effect through the different signaling pathways in vitro, their therapeutic efficacy is not well defined in vivo. The current study was carried out to investigate the combined antiviral effect in a model of mouse hepatitis virus Type 2 (MHV‐2) infection, in which fulminant hepatitis is developed. MHV‐2 was injected intraperitoneally into 4‐week‐old ICR mice, IFN or the vehicle was administered intramuscularly for 5 days, and the antiviral effect was evaluated based on survival periods, liver histology, serum alanine transaminase (ALT) levels, and MHV‐2 virus titers in the liver tissues. The animals in the group treated with a combination of IFN‐α and IFN‐γ survived for longer periods than the groups treated with IFN‐α alone and IFN‐γ alone (IFN‐α 10(3) (IU/mouse)/‐γ 10(3) vs. IFN‐α 10(3), P < 0.005; IFN‐α 10(3)/‐γ 10(3) vs. IFN‐γ 10(3), P < 0.001). This is consistent with the lower levels of hepatocellular necrosis and serum ALT and the decreased titers of MHV‐2 virus in the liver tissues (48 hr, P < 0.001; 72 hr, P < 0.001). These findings indicate that a combination of IFN‐α and IFN‐γ exhibits a synergistic antiviral effect on MHV‐2 infection. The biology of MHV‐2 is quite different from that of human hepatitis viruses; however, these results suggest the beneficial combined therapy of IFN‐α and IFN‐γ for the treatment of human viral hepatitis. J. Med. Virol. 69:188–194, 2003. © 2003 Wiley‐Liss, Inc.