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In Vivo Regulation of Hepatitis B Virus Biosynthesis by Peroxisome Proliferators and the Peroxisome Proliferator Activated Receptor

L.G. Guidotti, F.V. Chisari, C. Eggers, S.G. Zeitlin, H. Tang, F.F. Alcantara, A.K. Raney, A. McLachlan

Previously, we showed in cell cultures that the level of transcription from the nucleocapsid promoter of hepatitis B virus (HBV) is controlled by the nuclear hormone receptors retinoid X receptor and peroxisome proliferator activated receptor (PPAR). The finding that these receptors regulate the level of expression of HBV pregenomic RNA, the precursor of all viral replication intermediates, suggests that understanding the in vivo importance of these transcription factors in the viral life cycle might indicate that these receptors are suitable targets for antiviral agents. For this reason, we have started studies to establish the role of PPAR in the in vivo regulation of HBV transcription and replication.

We are using 2 approaches. First, HBV transgenic mice, which replicate HBV in their livers and kidneys, were treated with peroxisome proliferators, and the effects of the proliferators on viral transcription and replication were analyzed. In this case, the peroxisome proliferators, Wy-14,643 and clofibric acid, were introduced into the diets of the mice. Treatment with the peroxisome proliferators increased both HBV transcription and replication in the livers of the mice. The most pronounced effects were in the hepatocytes located in the region of the portal vein, where replication occurred only in the animals exposed to the peroxisome proliferators.

In the second approach, we used HBV transgenic mice that did not express PPAR. In these knockout mice, a high level of HBV replication in the liver extended farther from the central vein than in the normal HBV transgenic mice. This observation supports the idea that PPAR is involved in regulating HBV transcription and replication. In addition, the receptor appears to play a role in defining a gradient of HBV transcription across the hepatic lobule that governs the zone within the liver where significant viral replication occurs.

Analysis of HBV replication in the kidneys of PPAR knockout HBV transgenic mice indicated that PPAR can influence viral replication in a sex-dependent manner. Viral replication in the kidney of HBV transgenic mice is generally lower than that observed in the liver. In PPAR knockout HBV transgenic mice, viral replication appears to be enhanced in males but not in females, indicating sexual dimorphism in HBV replication in response to the loss of PPAR. The mechanisms that govern the different effects of PPAR on HBV transcription and replication are being investigated to determine the physiologically relevant ligands for this receptor. With this information, it may be possible to design synthetic ligands that can bind PPAR without activating viral transcription, and in this way, it may be possible to inhibit HBV replication in patients infected with the virus.