Dynamics of hepatitis C virus quasispecies turnover during interferon-alpha treatment.
Interferon-alpha (IFN) has been shown to accelerate the evolution of hepatitis C virus (HCV) variants (quasispecies) in nonresponder patients. Different sensitivities of HCV variants to IFN are discussed as a possible mechanism. In the present study, quasispecies were investigated in detail by a newly established and validated direct solid-phase sequencing of the hypervariable region 1 (HVR1), during the initial 3 months of IFN therapy. According to single strand conformation polymorphism (SSCP) analysis, 14 of 26 (54%) virologic nonresponders with quasispecies evolution were identified. Six representative patients with SSCP changes were selected for frequent HVR1 sequencing. Pre-existing variants were identified by cloning and sequencing of the pretreatment serum HCV sample. In one patient the major type was substituted by a minor variant within 3 days of treatment while in the majority of patients the pretreatment major type did not decline before days 26-57 of treatment. Total serum HCV RNA levels remained constant in all patients. In conclusion, although quasispecies evolution during IFN therapy is common, it occurs after a wide range of time intervals after initiation of therapy. Thus, nonresponse to IFN cannot exclusively be explained by changes in the quasispecies.
von Wagner
M
M
Innere Medizin II, Universitätskliniken des Saarlandes, Homburg/Saar, Germany.
Lee
J-H
JH
Rüster
B
B
Kronenberger
B
B
Sarrazin
C
C
Roth
W K
WK
Zeuzem
S
S
D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D004252:DNA Mutational Analysis; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation / Q000187:drug effects; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D018807:Polymorphism, Single-Stranded Conformational; D012367:RNA, Viral / Q000097:blood / Q000737:chemistry / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D019562:Viral Load; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics
D000998:Antiviral Agents; C400562:HVR1 protein, Hepatitis C virus; D016898:Interferon-alpha; D012367:RNA, Viral; D014764:Viral Proteins