Translational stop codons in the precore sequence of hepatitis B virus pre-C RNA allow translation reinitiation at downstream AUGs

Hepatitis B virus (HBV) wild-type pre-C RNA directs the synthesis of the HBeAg precursor but does not serve as mRNA for translation of the adjacent downstream C gene which encodes the core protein. Using bicistronic mRNA constructs that mimick pre-C RNA, we have demonstrated that this RNA likewise does not serve as messenger for translation of the P gene, which is located downstream of the C gene. However, when the pre-C RNA contains a translational stop codon at position 2 or 28 of the pre-C sequence (as in certain HBV mutants), it no longer directs synthesis of the HBeAg precursor but instead translation is initiated at downstream C and P gene AUGs. We propose that this occurs by a translation reinitiation mechanism.