A single nucleotide polymorphism in IL28B affects viral evolution of hepatitis C quasispecies after pegylated interferon and ribavirin therapy

Abstract

Interleukin-28B (IL28B) polymorphisms are associated with viral response to peginterferon and ribavirin (RBV) in chronic hepatitis C (HCV). Their recognition represents a breakthrough in the understanding of the role of the host in viral eradication. How these polymorphisms determine viral eradication is unknown. The IL-28B variants are hypothesized to have a differential impact on HCV quasispecies evolution during treatment with pegylated interferon (PEG-IFN) and RBV. In this study, HCV RNA levels were measured at early time points in 33 naïve genotype 1 hepatitis C patients and clonal analysis of the entire NS5A region was performed on sera from baseline and Day 7. Site rs12979860 polymorphisms were determined by direct sequencing of PCR products and classified into CC, CT, and TT and were identified in 13, 11, and 9 patients, respectively. The CC polymorphism more commonly was seen in Whites versus Blacks [12/21 (57%) vs. 1/12 (8%), P = 0.009] and HIV-infected versus mono-infected [13/25 (52%) vs. 0/8 (0%), P = 0.009]. Patients with CC and non-CC had similar baseline viral loads. More patients with the CC polymorphism had amino acid substitutions in NS5A compared to non-CC patients. Despite similar baseline viral diversity, by Day 7, significantly more patients with CC had higher non-synonymous substitution values compared to non-CC (P = 0.02). Chronic hepatitis C patients with the CC IL28B polymorphism have a higher number of amino acid substitutions in the NS5A region and early viral evolution due to greater interferon induced selective pressure during this critical period of treatment.