Amino acid variations in hepatitis C virus p7 and sensitivity to antiviral combination therapy with amantadine in chronic hepatitis C.
BACKGROUND
Formation of transmembrane ion channels by hepatitis C virus (HCV) p7 and abrogation of channel function by amantadine was demonstrated in vitro. The relevance of HCV p7 amino acid (aa) variations for response to antiviral therapy with amantadine is unknown.


METHODS
HCV p7 was sequenced in 86 individuals who were infected with HCV genotype 1. Thirty-six of 86 patients received amantadine within an interferon-alpha (IFN-alpha)-based antiviral therapy. Helical wheel modelling for HCV p7 was performed.


RESULTS
No significant correlation of overall aa variations within HCV p7 was observed with response to IFN-alpha-based therapy with amantadine in HCV genotype 1alpha/b infected patients. When analysis was restricted to non-conservative aa variations, a higher number of aa substitutions within complete HCV p7 and transmembrane helix 2 was associated with non-response in HCV-1b-infected patients receiving therapy with amantadine (P=0.015 and P=0.037, respectively), without amantadine (P=0.106 and P=0.118, respectively), and in the total cohort of HCV-1b-infected patients (P=0.00007 and P=0.011, respectively). Furthermore, substitution L20F was observed more often in non-responders than responders with HCV-1b infection and therapy with amantadine (P=0.099). By in silico modelling, aa 20 was located toward the p7 channel lumen. Substitution L20F may impair amantadine action by altering the shape of the ion channel pore.


CONCLUSIONS
Substitution L20F within HCV p7 may be associated with non-response to combination therapy specifically with amantadine in HCV-1b-infected patients. Non-responders with HCV-1b infection showed higher numbers of non-conservative aa variations within HCV p7 than responders, irrespective of the application of amantadine.
Mihm
Ulrike
U
Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Kirrberger Str., 66421 Homburg/Saar, Germany.
Grigorian
Natalia
N
Welsch
Christoph
C
Herrmann
Eva
E
Kronenberger
Bernd
B
Teuber
Gerlinde
G
von Wagner
Michael
M
Hofmann
Wolf-Peter
WP
Albrecht
Mario
M
Lengauer
Thomas
T
Zeuzem
Stefan
S
Sarrazin
Christoph
C
D000547:Amantadine / Q000494:pharmacology / Q000627:therapeutic use*; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D014644:Genetic Variation; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D008969:Molecular Sequence Data; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics*; D000086082:Viroporin Proteins
D000547:Amantadine; D000998:Antiviral Agents; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D014764:Viral Proteins; C088369:p7 protein, Hepatitis C virus; D000086082:Viroporin Proteins