Relationship of hepatitis C genotype 1 NS5A sequence mutations to early phase viral kinetics and interferon effectiveness.
The interferon (IFN) sensitivity-determining region (ISDR) of the hepatitis C virus (HCV) NS5A protein is controversially implicated in determining IFN-alpha-sustained viral response for HCV genotype 1-infected patients. Because the NS5A protein interferes with protein kinase antiviral activity, this study attempted to determine whether ISDR amino acid mutation number would correlate better with IFN effectiveness to inhibit virus production and elicit early virus clearance. Early viral kinetic data from 22 genotype 1-infected patients treated with high-dose IFN was compared with ISDR mutation number. IFN effectiveness and first-phase viral log decline correlated directly with ISDR mutation number (P=.02). Mean mutation number was higher among rapid responders (3.7+/-1.0; n=6) than among nonresponders (1.3+/-1.0; n=16) (P=.001). Also, second-phase viral log decline and calculated hepatocyte death rate correlated directly with ISDR mutation number (P=.01). This supports a dual effector role for NS5A, which regulates virus production and immune clearance early in therapy.
Schiappa
Deborah A
DA
Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. Schiappa@uic.edu
Mittal
Chetna
C
Brown
Jennifer A
JA
Mika
Brian P
BP
D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D007370:Interferon Type I; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase