Replication of the wild type and a natural hepatitis B virus nucleocapsid promoter variant is differentially regulated by nuclear hormone receptors in cell culture
H. Tang et al., Replication of the wild type and a natural hepatitis B virus nucleocapsid promoter variant is differentially regulated by nuclear hormone receptors in cell culture, J VIROLOGY, 75(19), 2001, pp. 8937-8948
A natural hepatitis B virus (HBV) variant associated with seroconversion fr
om HBeAg to anti-HBe antibody contains two nucleotide substitutions (A1764T
and G1766A) in the proximal nuclear hormone receptor binding site in the n
ucleocapsid promoter. These nucleotide substitutions prevent the binding of
the retinoid X receptor alpha (RXR alpha)-peroxisome proliferator-activate
d receptor alpha (PPAR alpha) heterodimer without greatly altering the effi
ciency of binding of hepatocyte nuclear factor 4 (HNF4) to this recognition
sequence. In addition, these nucleotide substitutions create a new binding
site for HNF1 Analysis of HBV transcription and replication in nonhepatoma
cells indicates that RXR alpha -PPAR alpha heterodimers support higher lev
els of pregenomic RNA transcription from the wild-type than from the varian
t nucleocapsid promoter, producing higher levels of wildtype than of varian
t replication intermediates. In contrast, HNF4 supports higher levels of pr
egenomic RNA transcription from the variant than from the wild-type nucleoc
apsid promoter, producing higher levels of variant than of wild-type replic
ation intermediates. HNF1 can support variant virus replication at a low le
vel but is unable to support replication of the wild-type HBV genome. These
observations indicate that the replication of wild-type and variant viruse
s can be differentially regulated by the liver-specific transcription facto
rs that bind to the proximal nuclear hormone receptor binding site of the n
ucleocapsid promoter. Differential regulation of viral replication may be i
mportant in the selection of specific viral variants as a result of an anti
viral immune response.