The use of reverse genetics in the mouse, allowing flexible gene manipulation, has been one of the most powerful tools in the last decade for the understanding of complex biological phenomena. Transgenic and knock-out animal models have yet been fruitfully used in the understanding of the molecular basis of several human diseases. ± 3 Notably, the pathobiology of human viruses has been productively studied in murine models even in the lack of infectivity. One paradigmatic example is Hepatitis B Virus transgenic models which have been instrumental in clarifying many steps of its life cycle and pathogenesis of related disease. A more complex scenario emerges from Hepatitis C Virus (HCV) transgenic mouse models which do not allow as yet unequivocal conclusions. In man, pathological changes associated with chronic HCV infection have been ascribed both to the immune response against the virus and to direct viral cytopathic effects. The relative contribution of these factors in the onset of the various HCV-related pathological phenotypes, such as liver steatosis, fibrosis, cirrhosis, intrahepatic lymphocyte infiltration and hepatocellular carcinoma, have been explored by transgenic approaches. In the majority of the HCV transgenic models developed so far, the expression of viral protein(s) does not challenge the immune system, because they are recognized as `self', as confirmed by the lack of anti-HCV antibody production in the transgenic mice. Has a direct cytotoxic effect been ascribed to specific viral product(s)? The rather contradictory results reported in the literature are summarized in Table 1 where the HCV transgenic mice, that have been developed so far, are listed along with their relative phenotypes, the promoters, the animal strains and the viral protein detection systems used by the various authors. The phenotypic changes described are dissimilar even when the sole core protein is taken in account. Moriya et al. ± 11 have shown that expression of the core protein, which was found localized into lipid droplets, nucleus and mitochondria, leads to extensive steatosis, increased oxidative stress, mitochondrial injury and ultimately hepatocarcinoma in aging mice. In a similar transgenic line, reported by Honda et al. a major consequence of core expression was a modification in the Fas-induced apoptotic response, but no liver morphological alterations in untreated animals were described. Finally, no liver pathology was observed in the HCV core transgenic mice reported by Pasquinelli et al. It is worth noting that similar contradictory results, in terms of modulation of cellular proliferation, transformation and have also been reported in cell culture system apoptotis. Transgenic animals carrying HCV sequences coding for other structural proteins were also generated. No liver damage was described in the case of transgenic mice expressing the envelope proteins, either E2 alone by Pasquinelli et al. or E1 and E2 by Koike et al. Interestingly, expression of E1 and E2 proteins driven by a HBV regulatory region, leads to extrahepatic expression which results in exocrinopathy involving the salivary and lachrymal glands, with lymphocyte infiltration and accumulation of fibrous tissues. This pathology resembles Sjogren's syndrome which has been found to be associated with chronic HCV infection in humans. Expression of the structural proteins core, E1 and E2 driven by an ubiquitous promoter, reported by Honda et al. leads to necrosis of hepatocytes that are surrounded by infiltrating lymphocytes. Moreover, these mice show an increased susceptibility to Fas-mediated injury. No liver pathological changes were observed in a similar transgenic line reported by Kawamura et al. who, however, limited their observations to 6-month-old animals. A recent report, by Lerat et al. showed that liver-specific expression of all HCV structural proteins (core, E1, E2 and p7) led, in aging mice, to steatosis, mitochondrial injury, increased sensitivity to oxidative stress and, at very low frequency, hepato-carcinoma (one mouse out of 42). In the same article the authors described different transgenic lines which express the entire HCV polyprotein. Although protein expression was not detectable in these mice, they presented extensive steatosis, tumor-associated fibrosis and higher frequency of hepato-carcinoma (five out of 37), suggesting that the viral non-structural proteins could contribute to tumorigenesis. Kohara and coworkers attempted to take into account the contribution of the immunological response in HCVrelated pathology, mimicking an acute infection by means of inducible transgenic mice. ± 23 Based on the Cre/loxP technology, they generated a transgenic mouse carrying the core-NS2 cDNA, whose expression is induced by infection with a Cre recombinase-expressing Adenovirus. The authors reported that HCV protein expression resulted in specific anti-HCV cytotoxic T-cell activities and development of a substantial hepatic pathology with increased levels of Alanine Aminotranferase (ALT). This liver injury appears to be mediated by T-cells because depletion of CD4+ and CD8+ lymphocytes protects the mice from hepatic damage. Contrary to chronic expression of HCV proteins, which was reported to lead to increased Fasmediated responses, a significant inhibition of Fas-induced cell death was observed after transient HCV expression, apparently correlating with a block in cytochrome c release Cell Death and Differentiation (2003) 10, S16 ± S18 a 2003 Nature Publishing Group All rights reserved 1350-9047/03 $25.00