Hepatitis c virus genetic variability and the presence of ns5b resistance-Associated mutations as natural polymorphisms in selected genotypes could affect the response to ns5b inhibitors

V. C. Di Maio, V. Cento, C. Mirabelli, A. Artese, G. Costa, B. S. Alcaro, C. F. Perno, F. Ceccherini-Silberstein

Research output: Contribution to journalArticle

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Abstract

Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed the NS5B polymerase genetic variability in circulating HCV genotypes/subtypes and its impact on the genetic barrier for the development of resistance to clinically relevant nucleoside inhibitors (NIs)/nonnucleoside inhibitors (NNIs). The study included 1,145 NS5B polymerase sequences retrieved from the Los Alamos HCV database and GenBank. The genetic barrier was calculated for drug resistance emergence. Prevalence and genetic barrier were calculated for 1 major NI and 32 NNI resistance variants (13 major and 19 minor) at 21 total NS5B positions. Docking calculations were used to analyze sofosbuvir affinity toward the diverse HCV genotypes. Overall, NS5B polymerase was moderately conserved among all HCV genotypes, with 313/591 amino acid residues (53.0%) showing>1% variability and 83/591 residues (14.0%) showing high variability (>25.1%). Nine NNI resistance variants (2 major variants, 414L and 423I; 7 minor variants, 316N, 421V, 445F, 482L, 494A, 499A, and 556G) were found as natural polymorphisms in selected genotypes. In particular, 414L and 423I were found in HCV genotype 4 (HCV-4) (n=14/38, 36.8%) and in all HCV-5 sequences (n≤17, 100%), respectively. Regardless of HCV genotype, the 282T major NI resistance variant and 10 major NNI resistance variants (316Y, 414L, 423I/T/V, 448H, 486V, 495L, 554D, and 559G) always required a single nucleotide substitution to be generated. Conversely, the other 3 major NNI resistance variants (414T, 419S, and 422K) were associated with a different genetic barrier score development among the six HCV genotypes. Sofosbuvir docking analysis highlighted a better ligand affinity toward HCV-2 than toward HCV-3, in agreement with the experimental observations. The genetic variability among HCV genotypes, particularly with the presence of polymorphisms at NNI resistance positions, could affect their responsiveness to NS5B inhibitors. A pretherapy HCV NS5B sequencing could help to provide patients with the full efficacy of NNI-containing regimens.

Original languageEnglish
Pages (from-to)2781-2797
Number of pages17
JournalAntimicrobial Agents and Chemotherapy
Volume58
Issue number5
DOIs
Publication statusPublished - 2014

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Hepatitis Viruses
Hepacivirus
Genotype
Mutation
Nucleosides
Nucleic Acid Databases
Drug Resistance

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases
  • Medicine(all)

Cite this

Hepatitis c virus genetic variability and the presence of ns5b resistance-Associated mutations as natural polymorphisms in selected genotypes could affect the response to ns5b inhibitors. / Di Maio, V. C.; Cento, V.; Mirabelli, C.; Artese, A.; Costa, G.; Alcaro, B. S.; Perno, C. F.; Ceccherini-Silberstein, F.

In: Antimicrobial Agents and Chemotherapy, Vol. 58, No. 5, 2014, p. 2781-2797.

Research output: Contribution to journalArticle

Di Maio, V. C. ; Cento, V. ; Mirabelli, C. ; Artese, A. ; Costa, G. ; Alcaro, B. S. ; Perno, C. F. ; Ceccherini-Silberstein, F. / Hepatitis c virus genetic variability and the presence of ns5b resistance-Associated mutations as natural polymorphisms in selected genotypes could affect the response to ns5b inhibitors. In: Antimicrobial Agents and Chemotherapy. 2014 ; Vol. 58, No. 5. pp. 2781-2797.
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abstract = "Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed the NS5B polymerase genetic variability in circulating HCV genotypes/subtypes and its impact on the genetic barrier for the development of resistance to clinically relevant nucleoside inhibitors (NIs)/nonnucleoside inhibitors (NNIs). The study included 1,145 NS5B polymerase sequences retrieved from the Los Alamos HCV database and GenBank. The genetic barrier was calculated for drug resistance emergence. Prevalence and genetic barrier were calculated for 1 major NI and 32 NNI resistance variants (13 major and 19 minor) at 21 total NS5B positions. Docking calculations were used to analyze sofosbuvir affinity toward the diverse HCV genotypes. Overall, NS5B polymerase was moderately conserved among all HCV genotypes, with 313/591 amino acid residues (53.0{\%}) showing>1{\%} variability and 83/591 residues (14.0{\%}) showing high variability (>25.1{\%}). Nine NNI resistance variants (2 major variants, 414L and 423I; 7 minor variants, 316N, 421V, 445F, 482L, 494A, 499A, and 556G) were found as natural polymorphisms in selected genotypes. In particular, 414L and 423I were found in HCV genotype 4 (HCV-4) (n=14/38, 36.8{\%}) and in all HCV-5 sequences (n≤17, 100{\%}), respectively. Regardless of HCV genotype, the 282T major NI resistance variant and 10 major NNI resistance variants (316Y, 414L, 423I/T/V, 448H, 486V, 495L, 554D, and 559G) always required a single nucleotide substitution to be generated. Conversely, the other 3 major NNI resistance variants (414T, 419S, and 422K) were associated with a different genetic barrier score development among the six HCV genotypes. Sofosbuvir docking analysis highlighted a better ligand affinity toward HCV-2 than toward HCV-3, in agreement with the experimental observations. The genetic variability among HCV genotypes, particularly with the presence of polymorphisms at NNI resistance positions, could affect their responsiveness to NS5B inhibitors. A pretherapy HCV NS5B sequencing could help to provide patients with the full efficacy of NNI-containing regimens.",
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AU - Mirabelli, C.

AU - Artese, A.

AU - Costa, G.

AU - Alcaro, B. S.

AU - Perno, C. F.

AU - Ceccherini-Silberstein, F.

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