Infection of five human liver cell lines by dengue-2 virus

Elevated serum transaminase levels of dengue patients indicate the possible impact of dengue virus infection on liver function. To elucidate the actio n of dengue virus infection in liver cells, an in vitro cell line system wa s established that mimicked the liver status of diverse clinical patients. Briefly, four hepatoma cell lines (HA22T, Huh7, Hep3B, and PLC) and one non malignant hepatocyte cell line (Chang liver) were included, representing va rious levels of tumorigenicity and differentiation. Our data showed that in these five cell lines, dengue-2 virus attached to each cell type equally w ell; however, this virus had higher replication rates and levels of virion production in differentiated Huh7, PLC, Hep3B, and Chang liver cells. Likew ise, a lower replication rate was observed in the de-differentiated HA22T c ells. Differentiation-related factors seem to play an important role in den gue virus replication. Further study showed that sodium butyrate (NaB, a di fferentiation inducer) treatment enhanced dengue virus replication in HA22T cells. Moreover, we found that the severity of morphologic aberration and the increase in aspartate aminotransferase (AST) levels correlated with the virus replication rate in the four infected hepatoma cells. In conclusion, we showed that dengue virus can infect diverse liver cells with differing replication efficiency, which causes cytopathic effects (CPEs) of diverse s everity. Among the CPEs, the increased AST levels correlated with the clini cal results from 24 dengue fever patients, who showed increased AST levels at the onset of fever. In summary, we find that dengue-2 virus replicates a ctively and causes severe CPEs in differentiated hepatoma cells. Factors re lated to differentiation as well as tumorigenicity seem to play critical ro les, though the mechanisms of action remain unclear. J. Med. Virol. 60:425- 431, 2000. (C) 2000 Wiley-Liss, Inc.