Increase in de novo HBV DNA integrations in response to oxidative DNA damage or inhibition of poly(ADP-ribosyl)ation

Abstract

Chronic infection with hepatitis B virus (HBV) is associated with an increased risk for the development of cirrhosis and hepatocellular carcinoma (HCC).C hronic hepatitis B virus (HBV) infection is one of the major etiologic factors in the development of hepatocellular carcinoma (HCC). 1,2 Epidemiologic studies have shown that chronic HBV-infection is associated with a 100-fold increase in the risk for HCC development relative to noncarriers, placing HBV in the forefront among known human carcinogens. 3,4 Several lines of evidence suggest that HBV is tolerated by infected hepatocytes that do not show overt pathogenic reactions to virus replication. Therefore, liver damage observed in acute or chronic hepatitis B infection is mainly caused by cellular immune responses, which play a key role in the control of HBV infection. 5 Continuous necrosis and liver cell regeneration in the inflammatory context provide the driving force for carcinogenic progression in HBV carrier livers by allowing the selection of mutated hepatocytes. The long latency period for the development of HCC reveals a multistaged mechanism, in which selection of progressively mutated hepatocytes occurs. Moreover, virus-host interactions have been related to the oncogenic properties of the virus. Tumor progression may also be promoted by the presence of viral gene products, such as the X protein, 6-8 or by overexpression and accumulation of the large envelope protein. 9 The inappropriate expression of a truncated form of the middle envelope protein produced from integrated viral sequences has also been reported. 10 A direct role for integration of a mammalian hepadnavirus in the development of HCC has been identified for the woodchuck hepatitis virus (WHV). Integrations of WHV DNA into the N-myc and c-myc protooncogenes have shown that WHV integration can activate cellular protooncogenes by enhancer or promoter insertion. 11,12 Molecular analysis of genomic DNA from human HCCs revealed the presence of clonally propagated viral DNA integrations and the majority of tumors from chronic HBV carriers harbor integrated viral DNA, often multiple copies per cell. [13][14][15][16] Although a cellular protooncogene that is commonly activated by HBV has not been identified, the high prevalence of HBV integrations at sites of chromosomal abnormalities, such as deletions, duplications, and chromosomal translocations, has suggested that the integration process may occur in a manner that promotes mutagenesis. 1,17,18 Studies on the natural history of integrations of duck hepatitis B virus (DHBV) have directly shown that hepadnavirus integrations

In Vivo Proliferation of Hepadnavirus-Infected Hepatocytes Induces Loss of Covalently Closed Circular DNA in Mice

“…23,24 We considered the possibility that part of the intrahepatic viral DNA detected toward the end of the study may have originated from integrations promoted in the course of hepatocyte turnover, as has been shown in cell culture and in the woodchuck system. 9,18,25 However, viral integrations did not accumulate in chronically infected tupaia hepatocytes serially transplanted into uPA mice. Integration frequency varies among hepadnaviruses and in different hosts, and this may have contributed to the absence of integrations in proliferating PTHs.…”

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

“…Defects or reduction in DNA repair processes generally result in susceptibility to cancer. Both hepatitis B virus and oxidative stress itself have been shown to interfere with DNA repair and may increase de novo HBV DNA integration [65,66] .…”

Reduced Expression of DNA Damage Repair Genes High Mobility Group Box1 and Poly(ADP-ribose) Polymerase1 in Inactive Carriers of Hepatitis B Virus Infection-A Possible Stage of Viral Integration

“…A hallmark of HBV infection is the formation of a stable non-integrative HBV-DNA minichromosome, the so-called covalently closed circular DNA (cccDNA) in hepatocyte nuclei, which act as template to generate all RNAs necessary for protein production and viral replication. Furthermore, integrations of linear double stranded HBV DNA (dsDNA) sequences in to host genome do occur in infected hepatocytes, particularly in the presence of DNA damage 5 and cell turnover. 6,7 The overlength pregenomic RNA (pgRNA) which act as a replication intermediate is reverse transcribed to form relaxed circular DNA (rcDNA), cccDNA as well as can produce truncated form of linear HBV dsDNA capable of integration.…”

“…16 In vitro studies have shown that inhibition of PARP1 activity resulted increased frequency of HBV integration where PARP1 has the potential to limit the occurrence of de novo HBV DNA integrations. 5 Notwithstanding the reported integration of HBV DNA in HCC, acute and chronic infections [17][18][19] and identification of a novel PARP1 binding sequence motif in HBV core promoter region which has potential to disrupt host DNA damage repair pathways, 20 no study has been done so far to evaluate the status of host DNA damage repair mechanisms in HBV mediated progressive liver diseases. Furthermore, the status of HBV pgRNA as viral replication intermediate has not been evaluated in HBV disease categories.…”