Codon Usage as a Possible Source of Sofosbuvir Genetic Resistance Bias in HCV Patients Infected with Different Genotypes

Hepatitis C virus (HCV) is responsible for liver chronic infections that in a high percentage of cases lead to cirrhosis and hepatocellular carcinoma. In the past, treatment consisted on a combination of pegylated interferon plus ribavirin. However, since 2012 a new wave in treatment options appears with the new family of drugs targeting viral components, the so-called direct-acting antivirals. Now we have a battery of drugs directed against viral protease (NS3/4A), polymerase (NS5B), and viral NS5A protein. Sofosbuvir, a nucleotide-analogue directed against viral polymerase is one of the most effective drugs against HCV. However, pathways for resistance acquisition are obscure. One mutation can be considered either a resistant-associated polymorphism (RAP) or a resistantassociated substitution (RAS) depending on the virus genotype. Thus, L159F is considered as a RAP in genotype 1b but as a RAS for genotypes 1a and 3. Previous studies propose differences in the NS5B structure from different genotypes as the leading cause for these genotype differences. However, other reasons could be triggering these disparities. In this short communication we analyzed sequences from two different cohorts of HCV-infected naive patients. From these data we show that codons coding for L159 and C316 amino acids are genotype-dependent and changes in these positions could be acquired differentially depending on the relative abundance of the corresponding tRNAs.