Possible role of cytotoxic T cells in acute liver injury in hepatitis C virus cDNA transgenic mice mediated by Cre/loxP system

A line of hepatitis C virus (HCV) transgenic mice was established previousl y that was mediated by Cre/loxP system using HCV cDNA, including core, E1, E2 and NS2 genes. Intravenous infection of a recombinant adenovirus that ex presses Cre DNA recombinase (AxCANCre) induced HCV structural protein expre ssion in the liver of transgenic mice. HCV core protein production and tran sgene recombination in the mouse liver were serially evaluated after AxCANC re infusion. Core proteins were expressed efficiently and transgene was alm ost completely recombined in the liver of mice after 3 days and then the le vels of both core protein production and transgene recombination decreased continuously for 28 days. However, 30.6% of the trans gene recombination re mained at 28 days and only 2.7% of core production remained at 28 days afte r infection. Compared with non-transgenic controls, the serum alanine amino transferase levels in transgenic mice were significantly higher 10, 14, and 21 days after adenovirus infection. Histological scoring also indicated se vere pathological changes in the liver of transgenic mice after adenovirus infection. AxCANCre infusion increased CD8(+) lymphocyte infiltration into the liver of transgenic mice compared with that of non-transgenic controls, furthermore, cytotoxic T lymphocytes (CTLs) isolated from transgenic mice during liver injury were specific for the HCV proteins. These results sugge st that HCV structural proteins expressed in the liver of transgenic mice e nhanced liver injury. HCV-specific CTLs may be to enhance hepatitis. Thus, the present HCV transgenic mouse model provides a useful model of liver inj ury due to HCV, and the host immune response may play a pivotal role(s) in the pathogenesis of HCV. J. Med. Virol. 62:308-377, 2000. (C) 2000 Wiley-Li ss, Inc.