Abstract
Hepatitis C virus genotype 1a (HCV-1a) comprises clades I and II. The Q80K polymorphism is found predominantly in clade I but rarely in clade II. Here, we investigated whether natural polymorphisms in HCV-1a clade II entailed structural protein changes when occurrence of the Q80K variant was simulated. Based on HCV-1a clade I and II protein sequences, the structure of the HCV-1a Q80K mutant NS3-4A was obtained by comparative modeling. Its physicochemical properties were studied by molecular dynamics simulations and network analysis. Results demonstrate that, in the presence of the K80 variant, clade II protease polymorphisms A91 and S/G174 led to variations in hydrogen bond occupancies. Structural analyses revealed differences in (i) flexibility of the H57 catalytic residue on the NS3 protease and (ii) correlations between amino acids on the NS3 protease and the NS4A cofactor. The latter indicated possible destabilization of interactions, resulting in increased separation of these proteins. The present findings describe how the relationships between different HCV-1a NS3 protease amino acid residues could affect the appearance of viral variants and the existence of distinct genetic barriers to HCV-1a isolates.
Highlights
Hepatitis C virus (HCV) represents a global public health threat due to its high rate of evolution to chronic infection and the lack of a vaccine to prevent infections [1]
Variability of the HCV genome poses a challenge for direct-acting antivirals (DAAs), because drug resistance represents the leading cause for the failure of antiviral therapy against HCV
To verify if K80+S91+N/S174 polymorphisms were more frequent in the same clade I sequences than based on a random distribution, we estimated the frequencies of K80+S91+N174 and K80+S91+S174 and compared the results with the frequency of clade I Q80+S91+N174 and Q80+S91+S174 polymorphisms
Summary
Hepatitis C virus (HCV) represents a global public health threat due to its high rate of evolution to chronic infection and the lack of a vaccine to prevent infections [1]. Effective therapeutic drugs directly targeting HCV proteins, the so-called direct-acting antivirals (DAAs), have been the subject of intense research in the last decade. HCV displays high genetic heterogeneity and great sequence variability, contributing to the existence of natural polymorphisms. HCV is present within patients as a quasispecies—variants that are closely related but heterogeneous [7]. Variability of the HCV genome poses a challenge for DAAs, because drug resistance represents the leading cause for the failure of antiviral therapy against HCV infections. The Q80K polymorphism is found predominantly in HCV genotype 1a (HCV-1a) sequences
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
