Hepatitis B virus mutations affecting synthesis of relaxed-circular viral DNA : Relation to disease severity

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There are three kinds of viral HBV DNAs, the single-stranded (SS) HBV DNA, the double-stranded linear (DL) HBV DNA and the double-stranded relaxed-circular (RC) HBV DNA, in HBV-infected cells. Among them, only the RC HBV DNA can form the mature HBV virion with infectivity. In this study, we investigated HBV mutations affecting RC HBV DNA synthesis and its involvement in the pathogenesis of HBV-related liver diseases.1) Identification of the accountable HBV mutation for an increase of RC HBV DNA synthesis in a patient with tvpe B chronic hepatitis showing lethal exacerbation.We experienced a patient with type B chronic hepatitis showing lethal disease exacerbation. From serum samples at 1 year before exacerbation (P1) and after exacerbation (P2), the full-length HBV DNAs were obtained and designated as HBV P1 and P2 strains. When the HBV P1 and P2 strains were expressed in the cultured cells, the RC HBV DNA level was higher in P2-expressing cells than in P1-expressing ones. Further deta … More iled analyses showed that a G-to-A mutation at nt 2790 from P1 to P2 was an accountable mutation for an increase of RC HBV DNA synthesis and the subsequent disease deterioration in this patient.2) Relation of HBV mutations affecting the the RC HBV DNA sythesis to the disease severity in type B acute and chronic liver disease.Thus far, three regions, α (nt2817-2936), γ (nt1909-2141) and δ (nt1373-1589), have been shown to be cis-acting elements which play an important role in RC HBV DNA synthesis. In this study, we carried out sequencing analysis of full-length HBV DNA in 44 patients with type B chronic liver disease and 15 patients with type B acute liver disease. The degree of mutations in the α, γ and δ regions was correlated with the disease severity. In patients with chronic liver disease, the degree of mutations in the α and δ regions was higher in patients with cirrhosis and hepatocellular carcinoma than in those with chronic hepatitis (p=0.006 and p=0.05). As for patients with acute liver disease, patients with fulminant hepatitis had the higher degree of mutations in the α, and γ regions than those with acute self-limited hepatitis (p=0.03 and p=0.01). These results suggest that the high degree of mutations within these regions may affect RC HBV DNA synthesis and viral replicative competence, resulting in the serious liver disease in both acute and chronic HBV infection. Less