title: Complexity and catalytic efficiency of hepatitis C virus (HCV) NS3 and NS4A protease quasispecies influence responsiveness to treatment with pegylated interferon plus ribavirin in HCV/HIV-coinfected patients.
abstract: The role of the hepatitis C virus (HCV) NS3/4A protease in ablating the signaling pathway involved in the production of alpha/beta interferon (IFN-α/β) suggests a relationship between NS3/4A proteolytic activity and a patient's response to IFN-based therapy. To identify viral factors associated with the HCV treatment response, we analyzed the pretreatment NS3/4A protease gene quasispecies composition of 56 HCV genotype 1-HIV-1-coinfected patients treated in our clinic with pegylated IFN (pegIFN) plus ribavirin (RBV). The catalytic efficiency of the dominant (i.e., the most abundant) quasispecies was also assayed for Cardif cleavage and correlated with treatment outcome. A total of 1,745 clones were isolated and sequenced. Significantly less nucleotide quasispecies heterogeneity and lower Shannon entropy values were detected within the responder group (P < 0.05). A correlation was also found between the efficiency of NS3/4A protease Cardif cleavage and therapy outcome. Proteases from sustained responder patients were more efficient at processing Cardif (mean ± standard error of the mean [SEM], 0.8960 ± 0.05568; n = 19) than proteases from nonresponders (mean ± SEM, 0.7269 ± 0.05306; n = 37; P < 0.05). Finally, the amino acid p distance (the proportion [p] of nucleotide sites at which two sequences being compared are different) was significantly shorter in patients with an interleukin-28B (IL-28B) risk allele (P < 0.01), suggesting that IL-28B risk allele carriers exert a lower positive selection pressure on the NS3/4A protease. NS3/4A protease efficiency in cleaving Cardif may be associated with the pegIFN-RBV treatment response, as shown in our cohort of HIV-HCV-coinfected patients. Greater NS3/4A nucleotide heterogeneity and higher Shannon entropy values in nonresponders suggest that less HCV quasispecies complexity may favor a better response to pegIFN-RBV.
authors.affiliation: Fundacio irsiCaixa, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Aparicio
authors.forename: Sandra
authors.initials: S
authors.lastname: Franco
authors.forename: Mariona
authors.initials: M
authors.lastname: Parera
authors.forename: Cristina
authors.initials: C
authors.lastname: Andrés
authors.forename: Cristina
authors.initials: C
authors.lastname: Tural
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Martínez
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification; D002384:Catalysis; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000821:virology; D015497:HIV-1; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006526:Hepatitis C / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011092:Polyethylene Glycols / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus