Abstract
Human hepatitis B virus (HBV) can cause chronic, lifelong infection of the liver that may lead to persistent or episodic immune-mediated inflammation against virus-infected hepatocytes. This immune response results in elevated rates of killing of virus-infected hepatocytes, which may extend over many years or decades, lead to fibrosis and cirrhosis, and play a role in the high incidence of hepatocellular carcinoma (HCC) in HBV carriers. Immune-mediated inflammation appears to cause oxidative DNA damage to hepatocytes, which may also play a major role in hepatocarcinogenesis. An additional DNA damaging feature of chronic infections is random integration of HBV DNA into the chromosomal DNA of hepatocytes. While HBV DNA integration does not have a role in virus replication it may alter gene expression of the host cell. Indeed, most HCCs that arise in HBV carriers contain integrated HBV DNA and, in many, the integrant appears to have played a role in hepatocarcinogenesis. Clonal expansion of hepatocytes, which is a natural feature of liver biology, occurs because the hepatocyte population is self-renewing and therefore loses complexity due to random hepatocyte death and replacement by proliferation of surviving hepatocytes. This process may also represent a risk factor for the development of HCC. Interestingly, during chronic HBV infection, hepatocyte clones detected using integrated HBV DNA as lineage-specific markers, emerge that are larger than those expected to occur by random death and proliferation of hepatocytes. The emergence of these larger hepatocyte clones may reflect a survival advantage that could be explained by an ability to avoid the host immune response. While most of these larger hepatocyte clones are probably not preneoplastic, some may have already acquired preneoplastic changes. Thus, chronic inflammation in the HBV-infected liver may be responsible, at least in part, for both initiation of HCC via oxidative DNA damage and promotion of HCC via stimulation of hepatocyte proliferation through immune-mediated killing and compensatory division.
Highlights
Integration of hepatitis B virus (HBV) DNA into the Chromosomal DNA of Hepatocytes iations.Hepadnaviruses have a relaxed circular partially doubled stranded DNA genome (RC-DNA) (Figure 1A) that is converted into a covalently closed circular DNA (CCC-DNA)during initiation of infection [1,2]
Using Model 4 (Figure 6), we found that maximum hepatocyte clone sizes measured using inverse-nested PCR assays for integrated HBV DNA were generally larger than predicted sizes for a range of hepatocyte death rates, which in our view supports the notion that the larger clones arose from cells with a selective growth or survival advantage
Practical Issues: Clonal expansion of hepatocytes is an implicit feature of liver biology which is driven by liver growth during childhood
Summary
Hepadnaviruses have a relaxed circular partially doubled stranded DNA genome (RC-DNA) (Figure 1A) that is converted into a covalently closed circular DNA (CCC-DNA). CCC-DNA is the template for viral RNA synthesis, including formation of the pre-genomic RNA (pgRNA) and mRNAs for the viral proteins. PgRNA is greater than unit length (Figure 1B) and is reverse transcribed to form virion. A small fraction of virions contains double-stranded linear DNA (DSL-DNA) (Figure 1C), formed by the reverse transcription pathway when the RNA primer for second strand (DNA dependent) DNA synthesis fails to translocate from DR1 to DR2 to prime formation of RC-DNA [3]. This DSL-DNA may be converted to aberrant forms of CCC-DNA by illegitimate recombination [4]. DSL-DNA may be converted to aberrant forms of CCC-DNA by illegitimate recombination [4]
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