Emergence of a novel mutation in the FLLA region of hepatitis B virus during lamivudine therapy.
The emergence of resistance to lamivudine has been one of the major stumbling blocks to successful treatment and control of hepatitis B virus (HBV) infections. The major mechanism of resistance has been attributed to the alteration in the YMDD motif of the HBV polymerase due to an amino acid change of rtM204 to V/I and an accompanying rtL180M conversion. A novel mutation pattern in a patient having clinical breakthrough under lamivudine therapy was discovered. The mutant had a rtL180C/M204I genotype and was detected after 2 years of therapy with lamivudine. To characterize this novel variant, site-directed mutagenesis was performed using a vector construct containing the HBV genome. Transient transfection studies in human hepatoma cells with HBV carrying the new mutant demonstrated that the rtL180C/M204I mutant was resistant to lamivudine up to 10 microM. The resistance profile was comparable to that of the previously reported rtL180 M/M204I-containing virus. These observations were further confirmed by generation of stable cultures transfected with the mutant virus.
Pai
S Balakrishna
SB
Veterans Affairs Medical Center, Medical Research 151 H, 1670 Clairmont Road, Decatur, Georgia 30033, USA.
Bozdayi
A Mithat
AM
Pai
Rekha B
RB
Beker
Tolunay
T
Sarioglu
Mustafa
M
Turkyilmaz
Ahmet R
AR
Grier
Jason
J
Yurdaydin
Cihan
C
Schinazi
Raymond F
RF
D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000032:analysis; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics*; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D008297:Male; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D004259:DNA-Directed DNA Polymerase