DIFFERENTIAL INHIBITION OF NUCLEAR HORMONE RECEPTOR DEPENDENT HEPATITIS B VIRUS REPLICATION BY SMALL HETERODIMER PARTNER

Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, IL 60612

^* To whom correspondence should be addressed. Email: mclach{at}uic.edu.

	Abstract

The nuclear hormone receptors, hepatocyte nuclear factor 4 (HNF4) and the retinoid X receptor (RXR) plus peroxisome proliferator-activated receptor (PPAR) heterodimer, support hepatitis B virus (HBV) pregenomic RNA synthesis and viral replication in nonhepatoma cells. Small heterodimer partner (SHP), an orphan nuclear hormone receptor lacking a DNA binding domain, inhibits nuclear hormone receptor-mediated viral transcription and replication. Inhibition of HBV replication by SHP is dependent on the presence of nuclear hormone receptors. HBV replication that is dependent on HNF4 is considerably more sensitive to SHP-mediated inhibition than RXR/PPAR directed viral biosynthesis. SHP inhibition of HBV biosynthesis in HepG2 cells suggests multiple nuclear hormone receptors mediate viral replication in this human hepatoma cell line. These observations suggest that the physiological regulation of HBV biosynthesis by SHP in the liver will depend on both the level of SHP expression and the relative contribution of HNF4 and RXR/PPAR, plus potentially additional nuclear hormone receptors, to HBV RNA synthesis and replication.