ABERRANT EXPRESSION OF A CYTOKERATIN IN A SUBSET OF HEPATOCYTES DURING CHRONIC WHV INFECTION

Chronic infection of woodchucks with woodchuck hepatitis virus (WHV) i nvariably leads, within 2-4 years, to the appearance of hepatocellular carcinoma (HCC). HCC is preceded by an extended period of chronic liv er damage, probably resulting from the immune response to viral antige ns. It may be that infection itself also induces changes in the hepato cyte population. To begin to identify some of the changes in the liver prior to the appearance of HCC, monoclonal antibodies (MAbs) were gen erated from mice immunized with hepatocytes from a woodchuck chronical ly infected with WHV or with a tumor lysate. Immunofluorescence micros copy was used to select MAbs that reacted with host markers whose patt erns of expression would distinguish chronically infected from uninfec ted liver or from liver tumors. One of these MAbs (2F2) reacted strong ly with a subset of hepatocytes in chronically infected liver; a simil ar staining pattern was not detected in uninfected or transiently infe cted liver. Evidence is presented that this strong staining reaction r eflects the overexpression or accumulation of the hepatocyte-specific intermediate filament protein, cytokeratin K18, a protein previously i mplicated in cryptogenic cirrhosis of the liver in humans (Ku, N. O., Wright, T. L., Terrault, N. A., Gish, R,, and Omary, M. B. J. Clin, in vest 99: 19-23, 1997). Double immunofluorescent staining with antibodi es to K18 and M-envelope protein of WHV suggested that strong reactivi ty to K18 was limited to cells expressing high levels of one or both o f the large viral-envelope proteins, M and L; however, high expression of these viral proteins was not always associated with a strong K18 s taining reaction. (C) 1998 Academic Press.