Mechanisms downstream of reverse transcription reduce serum levels of HBV DNA but not of HBsAg in chronic hepatitis B vi
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RESEARCH
Open Access
Mechanisms downstream of reverse transcription reduce serum levels of HBV DNA but not of HBsAg in chronic hepatitis B virus infection Simon B. Larsson*, Sebastian Malmström, Charles Hannoun, Gunnar Norkrans and Magnus Lindh
Abstract Background: Hepatitis B virus (HBV) DNA in serum of chronically infected patients declines by 3–4 log10 units at loss of HBe antigen (HBeAg) from serum. The mechanisms behind this decline, and the much smaller decline of surface antigen (HBsAg) levels, are still not well known. The aim of this study was to get a better understanding of this process by analysing both serum and intrahepatic markers of HBV replication. Methods: Levels of HBV DNA and HBsAg in serum, and covalently closed circular DNA (cccDNA), pregenomic RNA (pgRNA) and S-RNA and total intrahepatic HBV DNA (ihDNA) in liver biopsies from 84 chronically infected patients (16 positive and 68 negative for HBeAg) were analysed. Results: Lower HBV DNA levels within HBeAg-positive stage reflected lower levels of cccDNA and pgRNA with strong correlation. In HBeAg-negative patients, ihDNA levels were greater and HBV DNA levels in serum lower than expected from pgRNA levels. A lower HBV DNA/HBsAg ratio corresponded with lower pgRNA/cccDNA (p < 0.01) and higher S-RNA/cccDNA (p < 0.0001) ratios, suggesting that in HBeAg-negative patients transcription of pgRNA, but not of S-RNA, becomes suppressed. Conclusions: The marked reduction of HBV DNA in serum after loss of HBeAg appears to be due to combined reduction of cccDNA, pgRNA and yet unidentified mechanisms downstream of reverse transcription. Such mechanisms include faster clearance of circulating virus or blocked secretion of virions, the latter supported by the observed relative increase of ihDNA in HBeAg-negative patients. The smaller reduction of S-RNA than of pgRNA partly explains why HBsAg remain high in the HBeAg-negative stage, supporting the possibility of HBsAg synthesis from integrated HBV DNA. Keywords: HBV DNA, HBsAg, cccDNA, Replication, pgRNA
Background Despite the availability of an effective vaccine, chronic hepatitis B virus (HBV) infection remains an important cause of liver cirrhosis and hepatocellular carcinoma, in particular in East Asia and Sub-Saharan Africa [1]. In clinical diagnostics, HBV DNA levels in serum are the most important marker for the assessment of prognosis * Correspondence: [email protected] Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
and treatment outcome during chronic HBV infection. In early stage of chronic infection HBV DNA usually persists at high levels, above 7–8 log10 IU/mL, for many years, often decades. Later in life the HBV DNA levels decline when the immune response evolves to more efficiently suppress viral replication. The greatest reduction of HBV DNA is observed at loss of hepatitis B e antigen (HBeAg) from the blood, a critical step that typically represents a transition from high to low replicative stage, usually a
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