Acute liver injury following infection with a cytopathic strain of duck hepatitis B virus

Abstract

A variant avian hepadnavirus that has been shown to destroy hepatocytes in vitro was found to be cytopathic in vivo. A single amino acid change of glycine to glutamic acid at position 133 (G133E) in the preS protein of duck hepatitis B virus (DHBV) caused an increase in the intranuclear pool of viral covalently closed circular DNA (cccDNA), resulting in a transient elevation of viral replication and eventual hepatocyte destruction. In vivo viral infection with the G133E virus was compared with infection with wild-type virus over a 72-day period. Birds were inoculated with virus at day 2 post-hatch to ensure a high percentage of infected hepatocytes and potential persistence of virus. Birds infected with the G133E virus had increased periportal cellular proliferation and numerous lysed apoptotic hepatocytes following 100% infection of hepatocytes. The liver damage within G133E virus-infected birds subsided over time, resulting in mild chronic hepatitis that was similar to that observed within wild-type virusinfected birds. The subsidence of liver damage in G133E virus-infected birds coincided with a reduction of viral cccDNA to wild-type virus levels in the liver. Our study indicates that maintenance of wild-type levels of viral cccDNA promotes persistence of virus infection by establishing a noncytopathic infection. (HEPATOLOGY 1999;29:563-571.)Hepadnaviruses cause persistent productive infections of each infected hepatocyte. During the initiation of infection, the relaxed circular DNA (rcDNA) genome in the virion is converted to covalently closed circular DNA (cccDNA) in the nucleus. Viral cccDNA is used as the template for viral RNA transcription, resulting in the production of a viral RNA molecule (pregenome) that is greater than one genome in length. The RNA pregenome is encapsidated within a viral core particle, where it is reverse-transcribed by the viralencoded DNA polymerase to produce viral minus-strand DNA. 1 Plus-strand DNA synthesis is then carried out by the same viral DNA polymerase using the viral DNA minusstrand as a template. The final DNA product contained with the capsid is a double-stranded molecule that is held in a circular conformation by a short region of base-pairing between the 5Ј end of the two strands. This form of viral DNA is referred to as relaxed circular DNA, or rcDNA. The viral capsids that contain rcDNA associate with the viral envelope proteins at the endoplasmic reticulum and are secreted as virions. Alternatively, rcDNA molecules may enter into the nucleus of the infected hepatocyte, where they are converted to additional molecules of cccDNA and cause increased levels of viral replication. The production of new viral cccDNA is regulated by the viral large envelope protein (preS) by a mechanism that has not been biochemically defined. 2 Presumably, an interaction between the preS protein and rcDNAcontaining capsids is necessary for enveloped virus formation and promotes secretion of viral rcDNA from the hepatocyte as virions. Because defects in preS that specifically inhibit ...

Low Dynamic State of Viral Competition in a Chronic Avian Hepadnavirus Infection

“…We showed that a cytopathic mutant of DHBV is at a severe disadvantage during chronic infection in competition with the noncytopathic wild-type virus (10,11), and that under certain circumstances, a precore-minus mutant of DHBV is enriched over a wild-type virus (28). In this study, we determined the rate at which one strain of DHBV could be enriched over a slower replicating strain dur-ing chronic infection due to a growth-rate advantage.…”

Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primaryTupaiahepatocytes

“…First, a duck hepatitis B variant containing a single amino acid change in the large surface antigen resulting in accumulation of covalently closed circular DNA has resulted in a strong cytopathic effect in hepatocytes in vitro and in vivo. [37][38][39] In this system, the level of viral replication and covalently closed circular DNA formation correlated with cytopathic effects in infected hepatocytes. 37 Second, intracellular retention of the HBV large surface protein has been shown to induce apoptosis in cell lines.…”

Pathogenesis of hepatitis B virus infection

“…Although HBV is considered as a noncytopathic virus [14] , hepadnavirus-induced apoptosis and cytopathic effects have been described in several experimental model systems: First, a duck hepatitis B variant containing a single amino acid change in the large surface antigen resulting in accumulation of cccDNA resulted in a strong cytopathic effect in hepatocytes in vitro and in vivo [90][91][92] . In this system, the level of viral replication and cccDNA formation correlated with cytopathic effects in infected hepatocytes [90] .…”