PLoS ONE (Jan 2012)

HCV genotypes are differently prone to the development of resistance to linear and macrocyclic protease inhibitors.

  • Valeria Cento,
  • Carmen Mirabelli,
  • Romina Salpini,
  • Salvatore Dimonte,
  • Anna Artese,
  • Giosuè Costa,
  • Fabio Mercurio,
  • Valentina Svicher,
  • Lucia Parrotta,
  • Ada Bertoli,
  • Marco Ciotti,
  • Daniele Di Paolo,
  • Cesare Sarrecchia,
  • Massimo Andreoni,
  • Stefano Alcaro,
  • Mario Angelico,
  • Carlo Federico Perno,
  • Francesca Ceccherini-Silberstein

DOI
https://doi.org/10.1371/journal.pone.0039652
Journal volume & issue
Vol. 7, no. 7
p. e39652

Abstract

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BACKGROUND: Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed whether specific HCV-genotypes are differently prone to develop resistance to linear and macrocyclic protease-inhibitors (PIs). METHODS: The study includes 1568 NS3-protease sequences, isolated from PI-naive patients infected with HCV-genotypes 1a (N = 621), 1b (N = 474), 2 (N = 72), 3 (N = 268), 4 (N = 54) 5 (N = 6), and 6 (N = 73). Genetic-barrier was calculated as the sum of nucleotide-transitions (score = 1) and/or nucleotide-transversions (score = 2.5) required for drug-resistance-mutations emergence. Forty-three mutations associated with PIs-resistance were analyzed (36A/M/L/G-41R-43S/V-54A/S/V-55A-Q80K/R/L/H/G-109K-138T-155K/Q/T/I/M/S/G/L-156T/V/G/S-158I-168A/H/T/V/E/I/G/N/Y-170A/T-175L). Structural analyses on NS3-protease and on putative RNA-models have been also performed. RESULTS: Overall, NS3-protease was moderately conserved, with 85/181 (47.0%) amino-acids showing 94% HCV-2-4; 175L present in 100% HCV-1a-3-5 and >97% HCV-2-4). Furthermore, HCV-3 specifically showed non-conservative polymorphisms (R123T-D168Q) at two drug-interacting positions. Regardless of HCV-genotype, 13 PIs resistance-mutations were associated with low genetic-barrier, requiring only 1 nucleotide-substitution (41R-43S/V-54A-55A-80R-156V/T: score = 1; 54S-138T-156S/G-168E/H: score = 2.5). By contrast, by using HCV-1b as reference genotype, nucleotide-heterogeneity led to a lower genetic-barrier for the development of some drug-resistance-mutations in HCV-1a (36M-155G/I/K/M/S/T-170T), HCV-2 (36M-80K-155G/I/K/S/T-170T), HCV-3 (155G/I/K/M/S/T-170T), HCV-4-6 (155I/S/L), and HCV-5 (80G-155G/I/K/M/S/T). CONCLUSIONS: The high degree of HCV genetic variability makes HCV-genotypes, and even subtypes, differently prone to the development of PIs resistance-mutations. Overall, this can account for different responsiveness of HCV-genotypes to PIs, with important clinical implications in tailoring individualized and appropriate regimens.