Coevolution analysis of NS3, NS5A and NS5B proteins in all genotypes from hepatitis C virus (HCV)

CASTILLO ELIO R. D; TRIGO NICOLAS ; SALVATIERRA KARINA

Chicago

Congreso; Microbe 2020; 2020

Chronic infection caused by the hepatitis C virus (HCV) remains a public health problem worldwide. It is estimated that 3% of the world population are infected by this virus. In recent years, the development of direct-acting antivirals (DAAs) has increased, acting directly against viral proteins, such as the NS3 protease, the NS5A protein or the NS5B polymerase. However, although these new DAAs have demonstrated a potent antiviral effect in vitro and in vivo, the effects of DAAs are affected by the presence of resistance-associated substitutions (RASs).Resistance mutations that are detected in a protein can be accompanied by other compensatory mutations, for this reason it is important to determine if some RASs or compensatory polymorphisms co-evolve and contribute to resistance to DAAs.The aim of this work was to analyzed the co-evolution of amino acid positions at intra- and intermolecular level of genotypes 1 to 6 from HCV NS3, NS5A and NS5B proteins, based on sequences obtained from international databases.Different software, applications and computational algorithms were used to studied the complete proteic sequences repertory.Based on the intramolecular analysis of the three proteins, numerous amino acid positions were found in co-evolution. Our results suggest several positions in resistance to DAAs, in NS3 (positions 36, 80, 117, 122 and 174), in NS5A (positions 28, 30, 58, 62, 93 and 320), and in NS5B (positions 15, 300, 389, 421, 436 and 499). Only in the NS3 protein were some amino acids related to DAAs resistance were detected that co-evolve with compensatory positions (positions Thr72 and Gln86). In the intermolecular analysis, numerous positions in co-evolution were also detected.Our results suggest that amino acids related to DAAs resistance co-evolve with others, either intraprotein or interprotein, possibly to maintain viral fitness.Computational coevolution analysis allowed us to understand the proteic interaction network of the HCV involved in antiviral resistance. The identified co-evolving residues constitute a highly relevant predictions of protein-protein interactions and a subsequent experimental identification of HCV protein complexes. These procedure have a potential applicability in the analyses of other viral proteins and predictions of the associated protein interaction networks.Finally, based in our results we could suggest that certain substitutions of resistance in NS3 or NS5A, could favor the selection of resistance substitutions in NS5B, or vice versa.