Epistatic connectivity among HCV genomic sites as a genetic marker of interferon resistance.

Until recently, the standard-of-care therapy of patients with HCV infection involves treatment with interferon (IFN) and ribavirin (RBV). Host demographic and genetic factors as well as HCV genetic heterogeneity have been shown to be associated with outcomes of therapy. Although resistance to IFN/RBV remains an important clinical and public health problem, there are no reliable genetic markers for the prediction of the therapy outcomes. Recently, it was shown that adaptation to IFN, a major constituent of the host innate immunity, is reflected in the HCV genetic composition and epistatic connectivity among polymorphic genomic sites, thus providing novel genetic markers of IFN resistance. Consideration of coordinated evolution among HCV genomic sites allows for identification of these genetic markers from short regions of the HCV genome and for accurate prediction of therapeutic outcomes. HCV genomic co-evolution offers a general framework for the detection of predisposition to IFN resistance, and possibly to resistance to direct-acting antivirals.