Hepatocarcinogenicity of the woodchuck hepatitis virus.

Abstract

During investigations of the evolution of experimental laboratory infections of woodchucks (Marmota monax) with the woodchuck hepatitis virus (WHV), eight hepatocellular carcinomas (HCC) were observed, six in newborns and two in young adult animals, all within 17-36 months after infection. The absence of an external cocarcinogenic effect in the well-monitored woodchucks indicates the carcinogenicity of WHV and suggests the same for the genetically and biologically similar human hepatitis B virus (HBV). Laboratory infections of woodchucks with two strains of WHV, not reported here in detail, resembled human and chimpanzee HBV infections histologically and serologically. In these studies, eight woodchucks became carriers of surface antigen of WHV for >1 year. All eight woodchucks developed HCC, indicating a 100% risk of HCC in experimentally infected chronic WHV antigen carriers, which is analogous to the high risk of HCC in human hepatitis B surface antigen carriers. Histologically, the absence of cirrhosis in the examined pericarcinomatous tissue permits recognition of gradual transition from normal parenchyma to neoplastic nodules to HCC of rising anaplasia, indicating a continuum of increasingly more malignant neoplastic stages, as known for chemical carcinogenesis. The HCC developed in carrier woodchucks infected as newborns with only minor, if any, hepatitic changes but is associated with antigen-carrying hepatocytes and sometimes with hyperplastic nodules. This stage was preceded in infected adults by an early, acute, weeks-long hepatitis coinciding with the appearance of surface antigen. These findings are also analogous to typical HBV infection in human newborns and young adults, respectively. At the time of HCC development in all animals with adequate histologic material, an acute recent necroinflammation appeared around the tumor, associated with abnormal hematopoietic cells around and within the tumor. A promoting role in carcinogenesis of this necroinflammation of yet unestablished pathogenesis is being postulated, to be confirmed by determination of the status of the WHV DNA in the HCC and by prospective histologic study of the inflammatory reaction.Recently, several viruses have been associated with the induction of carcinomas in humans on epidemiologic and virologic evidence. This includes the Epstein-Barr virus in Burkitt lymphoma, the papilloma virus in cervical carcinoma, the group of human T lymphotropic viruses in lymphomas, and the hepatitis B virus (HBV) in hepatocellular carcinoma (HCC) (1). Despite the strong evidence for the carcinogenicity of these viruses, the requirement of a cocarcinogen is not fully excluded, although through the years this essentiality has become less probable. In chronic HBV infections, a potential role of aflatoxin (2, 3) is not excluded to date. HBV is a member of the hepadnaviruses, which show great homologies in DNA and its gene products but limited crossinfectivity (4, 5). In the eastern woodchuck (Marmota monax), in the Beechey ground squirrel in Cali...

Occult Lifelong Persistence of Infectious Hepadnavirus and Residual Liver Inflammation in Woodchucks Convalescent From Acute Viral Hepatitis

“…HCC ultimately developed in 2 of the 9 (22%) woodchucks within 35.5 and 56 months after apparent complete resolution of WHV infection. In the context of WHV strong tumorigenic potential, 29,30 this result is not surprising and provides further evidence that WHV genome persisted in the livers of the convalescent woodchucks. It also corroborates a previous report of HCC occurrence in woodchucks with recovery from acute WHV hepatitis.…”

Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection

“…WHV belongs to the genus Orthohepadnavirus (family: Hepadnaviridae), of which HBV is the prototype member. 11 Woodchucks with naturally acquired 12,13 or experimental 14,15 chronic WHV infection develop progressively severe chronic hepatitis and hepatocellular carcinoma (HCC), similar to the diseases observed in humans with chronic HBV infection. [11][12][13][14][15] The experiments reported here were designed to assess the antiviral activity of FIAU against WHV, and to determine the possible influence of hepadnavirus infection on toxicity by comparing the effects of FIAU in normal woodchucks and in chronic WHV carriers.…”

Duck hepatitis B virus infection, aflatoxin B1 and liver cancer in domestic Chinese ducks

“…WHV seems more oncogenic than HBV and other known hepadnaviruses, since 100% of woodchucks experimentally infected with this virus develop hepatocellular carcinoma (HCC) within [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] months after infection (Popper et al, 1987). In ground squirrels persistently infected with GSHV the latency is longer and the percentage of carriers developing HCC is lower (Marion et al, 1986).…”