Divergent activities of interferon-alpha subtypes against intracellular hepatitis C virus replication.
BACKGROUND
Interferon (IFN)-alpha is represented by several structurally related subtypes that show different antiviral and anti-tumor effects. Here, we analyzed differential effects of IFN-alpha subtypes on intracellular hepatitis C virus (HCV) replication using HCV subgenomic replicon system as a model.


METHODS
Huh7 and HeLa cells supporting expression of HCV replicon were treated with various concentrations of five recombinant human IFN-alpha subtypes 1, 2, 5, 8, and 10, and with IFN-alpha con1. The effects of IFNs on various cell-signaling pathways were assayed by using ISRE-, GAS-, AP1-, NF-kappa B-, CRE-, and SRE-luciferase reporter plasmids.


RESULTS
Each IFN-alpha subtype suppressed HCV replication in a dose-dependent manner. Among them, IFN-alpha8 was the most effective, while IFN-alpha1 was the least effective with 50% inhibitory concentrations of 0.123IU/ml versus 0.375IU/ml, respectively. These differential effects against HCV replication did not correlate with levels of the IFN-responsive ISRE or GAS reporter activities, nor they did activate the other reporters, AP1, NF-kappa B, CRE and SRE.


CONCLUSIONS
There were divergent effects of IFN-alpha subtypes against HCV replication that may be through JAK-STAT-independent pathways. Exploring further mechanisms of action may elucidate IFN-mediated cellular antiviral mechanisms.
Koyama
Tomoyuki
T
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, Japan.
Sakamoto
Naoya
N
Tanabe
Yoko
Y
Nakagawa
Mina
M
Itsui
Yasuhiro
Y
Takeda
Yoshie
Y
Kakinuma
Sei
S
Sekine
Yuko
Y
Maekawa
Shinya
S
Yanai
Yoshiaki
Y
Kurimoto
Masashi
M
Watanabe
Mamoru
M