TUMOR-NECROSIS-FACTOR-ALPHA AND INTERFERON-GAMMA INHIBIT SYNERGISTICALLY VIRAL REPLICATION IN HEPATITIS-B VIRUS-REPLICATING CELLS

The effects of tumor necrosis factor-alpha and/or interferon-gamma on the replication of hepatitis B virus were examined using HB611 cells. These cells were derived from human hepatoblastoma cells, Huh6, by int egrating hepatitis B virus DNA, and produce hepatitis B virus continuo usly. Each of the cytokines inhibited hepatitis B virus replication in the cells assessed as the amount of episomal hepatitis B virus DNA, w ithout a decrease in cell viability. When the two cytokines were admin istered together, the inhibitory effect became greater. Incubation of the cells with 1,000 U/ml tumor necrosis factor-alpha decreased HBV DN A replicative intermediates by 55%, and that with 1,000 U/ml interfero n-gamma decreased these by 51%. Furthermore, incubation with 1,000 U/m l tumor necrosis factor-alpha and 1,000 U/ml interferon-gamma in combi nation decreased HBV DNA replicative intermediates by 71%. In contrast , the amount of hepatitis B virus RNA and secretion of hepatitis B e a ntigen were not apparently reduced by the cytokines, and 2',5'-oligoad enylate synthetase activity was not detected in the supernatant. These results suggest that tumor necrosis factor-alpha and interferon-gamma inhibit hepatitis B virus replication by blocking some step in revers e transcription and that the 2',5'-oligoadenylate synthetase is not in volved in the mechanism underlying the inhibition by these two cytokin es. (C) 1995 Wiley-Liss, Inc.