EFFICIENT CONDITIONAL TRANSGENE EXPRESSION IN HEPATITIS-C VIRUS CDNA TRANSGENIC MICE MEDIATED BY THE CRE LOXP SYSTEM/

Conditional gene expression has greatly facilitated the examination of the functions of particular gene products, Using the Cre/loxP system, we developed efficient conditional transgene activation of hepatitis C virus (HCV) cDNA (nucleotides 294-3435) in transgenic mice, Efficien t recombination was observed in transgenic mouse liver upon intravenou s administration of adenovirus that expresses Cre DNA recombinase. Aft er transgene activation, most hepatocytes were stained with anti-core polyclonal antibody, and 21-, 37-, and 64-kDa proteins were detected b y Western blot analysis in liver lysates using anti-core, El, and E2 m onoclonal antibodies, respectively, Serum core protein was detected in transgenic mice 7 days after transgene activation with concurrent inc reases in serum alanine aminotransferase levels, Subsequently, an anti -core antibody response was detected 14 days after infection, Furtherm ore, a CD4 and CD8 positive cell depletion assay normalized both the s erum alanine aminotransferase increases and pathological changes in th e liver, These results suggest that HCV proteins are not directly cyto pathic and that the host immune response plays a pivotal role in HCV i nfection, Thus, this HCV cDNA transgenic mouse provides a powerful too l with which to investigate the immune responses and pathogenesis of H CV infection.