Abstract
Chronic infection by hepatitis B virus (HBV) genotype C is associated with a prolonged replicative phase and an increased risk of liver cancer, compared with genotype B infection. We previously found lower replication capacity but more efficient virion secretion by genotype C than genotype B isolates. Virion secretion requires interaction between core particles and ENVELOPE proteins. In the present study, chimeric constructs between genotype B and genotype C clones were generated to identify the structural basis for differential virion secretion. In addition to dimeric constructs, we also employed 1.1mer constructs, where the cytomegalovirus (CMV) promoter drove pregenomic RNA transcription. Through transient transfection experiments in Huh7 cells, we found that exchanging the entire envelope gene or just its S region could enhance virion secretion by genotype B clones while diminishing virion secretion by genotype C. Site-directed mutagenesis established the contribution of genotype-specific divergence at codons 108 and 115 in the preS1 region, as well as codon 126 in the S region, to differential virion secretion. Surprisingly, exchanging the envelope gene or just its S region, but not the core gene or 3′ S region, could markedly increase intracellular replicative DNA for genotype C clones but diminish that for genotype B, although the underlying mechanism remains to be clarified.
Highlights
The hepatitis B virus (HBV) causes acute and chronic infection of the liver, with the latter being a global public health problem because of its widespread distribution and severe sequelae, including liver cirrhosis and hepatocellular carcinoma (HCC) [1,2]
Genotype B infection is associated with a higher risk of fulminant hepatitis and acute exacerbation of chronic infection [14,15,16]
The objective of this study was to identify the structural basis for more efficient virion secretion by genotype C than genotype B
Summary
The hepatitis B virus (HBV) causes acute and chronic infection of the liver, with the latter being a global public health problem because of its widespread distribution and severe sequelae, including liver cirrhosis and hepatocellular carcinoma (HCC) [1,2]. Numerous epidemiological studies suggest that genotype C is more pathogenic than genotype B due Viruses 2017, 9, 62; doi:10.3390/v9040062 www.mdpi.com/journal/viruses. Genotype B infection is associated with a higher risk of fulminant hepatitis and acute exacerbation of chronic infection [14,15,16]. Comparative studies of the biological properties between these two major HBV genotypes could help gain a better understanding of the molecular basis for their different clinical outcomes. We cloned full-length genotype B and genotype
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