title: Conditional gene expression in hepatitis C virus transgenic mice without induction of severe liver injury using a non-inflammatory Cre-expressing adenovirus.
abstract: We previously established inducible-hepatitis C virus (HCV) transgenic mice, which expressed the HCV gene (nucleotides 294-3435) encoding the core, E1, E2, and NS2 proteins. The expression of these proteins is regulated by the Cre/loxP system and an adenovirus vector (AdV) that expresses Cre DNA recombinase (Cre) controlled by the CAG promoter (AxCANCre). Recent studies have demonstrated that AxCANCre injection alone results in severe liver injury by induction of the adenovirus protein IX (Ad-pIX) gene. As a result, HCV protein expression in transgenic mice livers was only short-term. In contrast, the EF1α promoter-bearing AdV induces slight Ad-pIX gene expression without inducing severe liver injury. Therefore, in the present study, we developed a Cre-expressing AdV that bears the EF1α promoter (AxEFCre) to express HCV protein in the transgenic mouse livers. In the non-transgenic mice injected with AxCANCre, alanine aminotransferase (ALT) levels were elevated and severe liver inflammation occurred; this was not observed in AxEFCre-injected mice. In contrast, AxEFCre-injected HCV transgenic mice showed milder liver inflammatory responses that were clearly due to HCV protein expression. Moreover, the AxEFCre injection enabled the transgenic mice to persistently express HCV protein. These results indicate that use of AxEFCre efficiently promotes Cre-mediated DNA recombination in vivo without a severe hepatitis response to AdV. This inducible-HCV transgenic mouse model using AxEFCre should be useful for research on HCV pathogenesis.
authors.affiliation: Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 1-6, Kamikitazawa 2-chome, Setagaya-ku, Tokyo 156-8505, Japan. chiyo-tm@ncnp.go.jp
authors.forename: Tomoko
authors.initials: T
authors.lastname: Chiyo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sekiguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hayashi
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Tobita
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kanegae
authors.forename: Izumu
authors.initials: I
authors.lastname: Saito
authors.forename: Michinori
authors.initials: M
authors.lastname: Kohara
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression; D005822:Genetic Vectors; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000473:pathology / Q000821:virology; D019426:Integrases / Q000378:metabolism*; D008099:Liver / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: C045073:Cre recombinase; D019426:Integrases