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Journal of Virology, October 2001, p. 8937-8948, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.8937-8948.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Replication of the Wild Type and a Natural Hepatitis B Virus Nucleocapsid Promoter Variant Is Differentially Regulated by Nuclear Hormone Receptors in Cell Culture†

Hong Tang, Anneke K. Raney, and Alan McLachlan*

Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037

Received 20 March 2001/Accepted 8 June 2001

A natural hepatitis B virus (HBV) variant associated with seroconversion from HBeAg to anti-HBe antibody contains two nucleotide substitutions (A1764T and G1766A) in the proximal nuclear hormone receptor binding site in the nucleocapsid promoter. These nucleotide substitutions prevent the binding of the retinoid X receptor alpha  (RXRalpha )-peroxisome proliferator-activated receptor alpha  (PPARalpha ) heterodimer without greatly altering the efficiency 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 RXRalpha -PPARalpha heterodimers support higher levels of pregenomic RNA transcription from the wild-type than from the variant nucleocapsid promoter, producing higher levels of wild-type than of variant replication intermediates. In contrast, HNF4 supports higher levels of pregenomic RNA transcription from the variant than from the wild-type nucleocapsid promoter, producing higher levels of variant than of wild-type replication intermediates. HNF1 can support variant virus replication at a low level but is unable to support replication of the wild-type HBV genome. These observations indicate that the replication of wild-type and variant viruses can be differentially regulated by the liver-specific transcription factors that bind to the proximal nuclear hormone receptor binding site of the nucleocapsid promoter. Differential regulation of viral replication may be important in the selection of specific viral variants as a result of an antiviral immune response.

* Corresponding author. Mailing address: Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8097. Fax: (858) 784-2513. E-mail: mclach{at}scripps.edu.

dagger Publication 13968-CB from The Scripps Research Institute.

Journal of Virology, October 2001, p. 8937-8948, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.8937-8948.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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