The “metabolovirus” model of hepatitis B virus suggests nutritional therapy as an effective anti-viral weapon

Abstract

Hepatitis B virus (HBV) is a small DNA virus that targets the liver almost exclusively. Chronic infection with HBV might lead to severe liver-related pathologies including chronic hepatitis, cirrhosis and hepatocellular carcinoma. Based on its enhancer composition, which links nutritional signals that control hepatic glucose and fat metabolism in the liver to HBV gene expression and replication, it appears that the virus has adopted a regulatory system that is unique to the major hepatic metabolic genes. This unique virus-host interaction, mediated by metabolic events in the liver, is designated by us the "metabolovirus model". We hypothesize that by mimicking the expression of key genes implicated in glucose homeostasis, HBV sophisticatedly exploits the host resources to ensure its persistence. Specifically, by recruiting transcription factors and coactivators common to essential hepatic metabolic genes the virus avoids a possible resistance by its host, on the one hand, and ensures a timely and proper response to changes in its environment in terms of metabolic milieu, on the other hand. Furthermore, by coupling its gene expression to the expression of hepatic metabolic genes that fluctuate during the day, we predict a fluctuating nature of HBV gene expression. This can serve the virus in its attempts to escape the host immune system in addition to other immune evading strategies adopted by the virus, such as the secretion of the e antigen. Based on our "metabolovirus model", we suggest new mechanisms to previously unexplained clinical phenomena, such as the observed diversity in disease severity between different geographical areas that differ in nutritional habits. Furthermore, given the up-regulatory effect of food deprivation on HBV gene expression and replication, we suggest that conditions of short-term starvation should be completely avoided by HBV-infected individuals, and dietary recommendations such as the ingestion of complex carbohydrates before sleep should be adopted. Thus, our hypothesis sets the stage for viral manipulation by controlling food intake, and opens additional avenues towards food or nutritional therapy as an effective anti-HBV weapon.