Retinoids: The Link Between Alcohol and Interferon?

Abstract

O ne of the greatest accomplishments in the history of the field of hepatology is the 25-year effort that led from the discovery of the hepatitis C virus (HCV) to the understanding of its life cycle and ultimately the development of highly effective targeted therapy. Perhaps less well appreciated is the extent to which the global scientific effort against HCV has transformed our knowledge of liver disease, host-viral interactions, and antiviral immune responses. Among these insights are the understanding of the reversibility of cirrhosis, the prognostic interpretation of liver histology, and the genesis of hepatocellular carcinoma. However, of all the scientific fruits of HCV research, none have been as significant as the profound insights gained into the nature of the antiviral interferon (IFN) pathway and the factors that determine its efficacy in different individuals. Although the development of new anti-HCV drugs has reached a state of maturity, basic scientific understandings of the nature of the livervirus interaction continue to emerge.One of the central issues that remain unresolved is the relationship between HCV and alcohol consumption. It is well documented that HCV and alcohol each exacerbate liver injury caused by the other, but even more profound is the observation that alcohol consumption leads to a more than seven-fold increase in the rate of virological failure of IFN treatment. (1) In spite of these strong clinical data, the mechanisms responsible for this effect are poorly understood-and their relevance, if any, to IFN-free treatment regimens is unknown.Interferons generated by hepatocytes in response to viral infection both clear virus from infected cells and make uninfected cells resistant to infection. In the case of HCV, the viral RNA is recognized by the pattern receptor and RNA helicase, RIG-I, and this triggers a signaling cascade involving the adapter protein MAVS, the downstream kinases TBK1 and IKKe, and the transcription factors IRF3 and IRF7. In hepatocytes, this results in the secretion of IFN-b. This process engages the effector arm of the IFN pathway where type 1 IFN binding to the receptors INFAR1 and IFNAR2 results in activation of the receptor-bound kinases TYK2 and JAK1. These in turn cause tyrosine phosphorylation of STAT1 and STAT2, which then form a heterotrimeric complex of pSTAT1, pSTAT2, and IRF9. This IFN-stimulated gene factor 3 is the active transcription factor that binds many IFN-sensitive response elements (ISREs) inducing IFN-stimulated genes (ISGs) that suppress viral replication by multiple mechanisms. Prior to the development of direct-activing antivirals, HCV therapy was almost wholly based on trying to activate this endogenous method to clear the virus. Endogenous IFN responses still determine the outcome of acute infections and may even play some role in direct-activing antiviral efficacy.Initially, there was little understanding of how alcohol affected IFN responses, but as replicon and in vitro infectious virus models of HCV became available, multiple e...