PGC-1α controls hepatitis B virus through nutritional signals

Hepatitis B virus (HBV) is a 3.2-kb DNA virus that replicates preferentially in the liver. Liver-enriched nuclear receptors (NRs) play a major role in the HBV life cycle, operating as essential transcription factors for viral gene expression. Notably, these NRs are also key players in metabolic processes that occur in the liver, serving as central transcription factors for key enzymes of gluconeogenesis, fatty acid beta-oxidation, and ketogenesis. However, the association between these metabolic events and HBV gene expression is poorly understood. Here we show that peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha), a major metabolic regulator and a coactivator of key gluconeogenic genes, robustly coactivates HBV transcription. We further demonstrate that the liver-enriched NR hepatocyte nuclear factor 4 alpha that binds HBV plays an important role in this process. Physiologically, we show that a short-term fast that turns on the gluconeogenic program robustly induces HBV gene expression in vivo. This induction is completely reversible by refeeding and depends on PGC-1 alpha. We conclude that HBV is tightly regulated by changes in the body's nutritional state through the metabolic regulator PGC-1 alpha. Our data provide evidence for nutrition signaling to control viral gene expression and life cycle and thus ascribe to metabolism an important role in virus-host interaction.