Transgenic Mouse Expressing a Full‐length Hepatitis C Virus cDNA

Abstract

Hepatitis C virus (HCV), a major causative agent of post transfusion non-A, non-B hepatitis (NANBH), can only infect humans and chimpanzees. We produced nine transgenic mouse lines carrying a full-length HCV cDNA with the human serum amyloid P component (hSAP) promoter that can direct liver-specific expression. In one of these lines HCV mRNA and HCV core protein were detected in the liver of the transgenic mouse, although the levels of expression were very low. In addition, HCV-related antibody was detected in the serum.Key words: Hepatitis C virus -Transgenic mouse -Human serum amyloid P component (hSAP) promoter Hepatitis C virus (HCV) is the most important etiological agent of post-transfusion non-A, non-B hepatitis (NANBH) 1) and is a major cause of chronic liver disease and hepatocellular carcinoma. HCV is distantly related genetically to both the pestiviruses and flaviviruses. The HCV genome is about 9.4 kb in length and consists of a highly conserved 5′ untranslated region followed by a single open reading frame that encodes a polyprotein of 3010 to 3033 amino acids.2-4) The host signal peptidase mediates the cleavage of a basic, putative nucleocapsid protein (C) from the N terminal of the polyprotein precusor, followed by two glycoproteins (E1, E2), both of which represent potential components of the viral envelope. 5-7)Various putative nonstructural proteins (NS2-5) are processed from the downstream region of the polyprotein, mediated in part by a viral protease encoded within the NS3 domain. [7][8][9][10] There is a need to develop vaccines and other antiviral therapies against HCV. A major reason for the lack of rapid progress is the absence of a convenient or inexpensive animal model for propagating HCV. As host animals are limited to humans and chimpanzees, there have been several attempts to develop in vitro HCV replication systems and in vivo infection or expression models. The former include in vitro replication systems using human T cells, [11][12][13][14][15][16][17][18][19] human fibroblasts, 20) human peripheral blood mononuclear cells, 21) non-neoplastic human hepatocytes, 12,22) human hepatoblastoma cells, 23) chimpanzee primary hepatocytes 24) and other cells. [25][26][27] Such HCVinfected culture systems will be useful for various biological studies, including investigations into the mechanisms of HCV replication of the viral genome and cellular tropism of HCV 12,15,16,19,[25][26][27] and into the structure of viral particles.17, 18, 24) Advances in in vivo infection models for reproducible propagation of HCV and hepatitis C viremia have been achieved either by transplantation of HCVinfected liver fragments from patients into BNX (beige/ nude/X-linked immunodeficient) mice 28) or intravenous injection of HCV DNA using gene delivery systems. 29,30) However, there is not enough information about the mechanism of viral persistence, the cellular tropism of HCV, or its pathogenicity in vivo. Another approach to elucidate these questions, including in vivo behavior, would be to establish a tran...

Repeated hepatocyte injury promotes hepatic tumorigenesis in hepatitis C virus transgenic mice

“…14,26) However, the development of HCC has not been observed in other studies in which transgenic mice harboring HCV core, structural or fulllength genes were investigated. [27][28][29][30][31] Likewise, a higher incidence of steatosis was not observed in the present experiment when transgenic mice were compared with non-transgenic mice. Moreover, HCC was not observed in any of the transgenic mice by 24 months of age.…”

Virus-Specific Cofactor Requirement and Chimeric Hepatitis C Virus/GB Virus B Nonstructural Protein 3

“…Unfortunately, small and relatively inexpensive animal models that support HCV replication are not available at the present time. Efforts to establish transgenic mouse models or xenografted SCID-hu mouse models have not yielded any reliable or convincing animal models that are suitable for anti-HCV drug development (8,36,45). The only animal model permissive for HCV infection in vivo is the chimpanzee, which is prohibitively expensive for routine drug discovery efforts.…”

Molecular Mechanism of Viral Hepatocarcinogenesis

“…They fail to demonstrate a direct role of HCV in the induction of HCC, however. The strains with the HCV core gene reported by others had a very low expression of viral core protein that was hardly detectable by anti-HCV core antibodies in a wide clinical use [18][19][20][21]. With such a poor expression of HCV core protein, the development of HCC is hardly expected.…”