Elevated serum transaminase levels of dengue patients indicate the possible impact of dengue virus infection on liver function. To elucidate the action of dengue virus infection in liver cells, an in vitro cell line system was established that mimicked the liver status of diverse clinical patients. Briefly, four hepatoma cell lines (HA22T, Huh7, Hep3B, and PLC) and one nonmalignant hepatocyte cell line (Chang liver) were included, representing various levels of tumorigenicity and differentiation. Our data showed that in these five cell lines, dengue-2 virus attached to each cell type equally well; however, this virus had higher replication rates and levels of virion production in differentiated Huh7, PLC, Hep3B, and Chang liver cells. Likewise, a lower replication rate was observed in the de-differentiated HA22T cells. Differentiation-related factors seem to play an important role in dengue virus replication. Further study showed that sodium butyrate (NaB, a differentiation 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 severity. Among the CPEs, the increased AST levels correlated with the clinical 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 actively and causes severe CPEs in differentiated hepatoma cells. Factors related to differentiation as well as tumorigenicity seem to play critical roles, though the mechanisms of action remain unclear.
Copyright 2000 Wiley-Liss, Inc.