Are there any subgenomic forms of hepatitis C virus RNA in the liver?

BACKGROUND

Hepatitis C virus has a single stranded positive RNA genoma. Although believed to replicate via semi-conservative transcription of a negative-stranded, genomic-length RNA intermediate, detailed steps of its replicative cycle are unknown.

AIMS

To quantify some of intrahepatic hepatitis C virus RNA forms, as inferred from comparison with replication of other members of the Flaviviridae family.

PATIENTS AND METHODS

Genomic and negative-stranded hepatitis C virus RNA were semi-quantitated by strand-specific reverse transcriptase-polymerase chain reaction at both their 5' and 3' ends in liver of 10 patients with recurrent hepatitis C after liver transplantation.

RESULTS

Our data are consistent with the existence of hitherto unrecognized, very large amounts (up to approximately 10,000 fold the amount of the replication intermediate proper) of subgenomic hepatitis C virus RNAs of genomic polarity, starting in the 5' untranslated region, of unknown length. Similarly, subgenomic RNAs of negative polarity, starting in the 3' untranslated region, may also be produced, albeit to a less extent. We found no correlation between the amount of these forms and any clinical, histological or virological feature. However, the number of subgenomic RNA molecules of negative polarity tended to be inversely correlated with viraemia (r = 0.7, p = 0.058), suggesting their possible role in controlling rate of virion production.

CONCLUSIONS

Hepatitis C virus replication results in transcription of huge amounts of subgenomic RNAs both of genomic and negative polarity, which may either regulate translation of excess structural antigens of hepatitis C virus, or play the role of defective RNAs interfering with viral replication. A revised model of hepatitis C virus RNA replication is proposed.