Molecular aspects of persistent woodchuck hepatitis virus and hepatitis B virus infection and hepatocellular carcinoma

Abstract

It seems evident that the development of fully malignant HCC is a multistage process with many variables. One possible mechanism by which many of these variables may interact is as follows. During chronic active hepatitis, viral DNA integration occurs randomly and at a low frequency in hepatocytes. Integration may be stimulated by the increased rate of hepatocyte cell division resulting from liver necrosis and regeneration during chronic disease. The presence of viral integrations in the cellular genome provides focal points for the generation of chromosomal aberrations. One pathway by which these aberrations may be generated involves rearrangement of integrated viral and cellular sequences following viral DNA integration. The rearrangements which occur may include deletion, translocation, transposition or amplification of specific viral and cellular DNA sequences. We and others have directly demonstrated that all of these events are associated with different HBV integrations. The presence of viral integrations in chromosomes may also, by some unknown mechanism, destabilize those chromosomes such that whole chromosomes fail to segregate and are lost from particular cells. Preliminary studies we have conducted using restriction fragment length polymorphisms have revealed the loss of Chromosome 11 alleles in several HCC, indicating that chromosome loss may be a common occurrence in HCC. Our studies with restriction fragment length polymorphisms support such a mechanism involving Chromosome 11 in HCC. Specific chromosomal aberrations associated with all HCCs have not yet been identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatocellular carcinoma in woodchuck hepatitis virus-infected woodchucks: Presence of viral DNA in tumor tissue from chronic carriers and animals serologically recovered from acute infections

“…This study, as well as previous reports (9. 27: 35-38). 40), demonstrates that the woodchuck is also suitable as an experimental virus infection model for the determination of risk factors for HCC development associated with hepadnavirus infection.…”

Treatment of Duck Hepatitis B Virus by Antisense Poly-2′-O-(2,4-Dinitrophenyl)-Oligoribonucleotides

“…The only available treatment for chronic hepatitis B is interferon-a (IFN-a), which has less than 50% efficacy even in highly selected patients. It also has been shown that the HBV infection could relate to later hepatocellular carcinoma (Tiollaia et al, 1985;Rogler et al, 1987;Offensperger et al, 1994). HBV belongs to the hepadnavirus family, which also includes woodchuck hepatitis virus (WHV), ground squirrel hepatitis virus (GSHV), and duck hepatitis B virus (DHBV) (Mason et al, 1980;Cullen et al, 1989).…”

“…The plus strand usually is not completed before the coating of the nucleocapsids. In chronic infection hosts, the integrated DNA has been detected (Rogler et al, 1987), and liver histologie changes have been reported (Freiman et al, 1988). Because the viral infection is considered to be an acquired genetic disease (Anderson, 1992;Morgan and Anderson, 1993), with the overexpression or expression of the acquired genes, it could also be used in the therapeutic treatment by gene blocking at either the transcription or translation level.…”

Hepatocytic expression of human sodium-taurocholate cotransporting polypeptide enables hepatitis B virus infection of macaques

“…Multiple animal models of HBV infection have been utilized over the past four decades including the Peking duck 4 , 5 , woodchuck 6 – 8 , mouse 9 , 10 , and chimpanzee 11 – 13 . These models have contributed significantly to our understanding of virus-host interactions, but each have drawbacks that limit their utility for drug development.…”