Sensitivity of L-(-)2,3-dideoxythiacytidine resistant hepatitis B virus to other antiviral nucleoside analogues.
L-(-)2',3'-Dideoxythiacytidine (L(-)SddC, Lamivudine) resistant hepatitis B virus (HBV) develops in patients after prolonged treatment. Point mutations detected in the viral genome from these patients have been shown to be responsible for L(-)SddC resistance. Therefore, new drugs active against L(-)SddC resistant HBV are needed. Using a transient transfection system, we studied the sensitivity of L(-)SddC resistant HBV to other anti-HBV nucleoside analogues. It was found that the L526M mutation alone caused greater resistance to penciclovir (PCV) than did the V553I mutation alone. Both mutations also caused the virus to be less sensitive to L(-)SddC and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU), although the degree of resistance was much less than that to PCV. The A546V mutation had no impact on the sensitivity to L(-)SddC, L-FMAU, and PCV. When these single mutations were coupled with the M550V/I mutation, all the double mutants were resistant to those drugs. Although 2',3'-dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine (L(-)Fd4C) was also less active, the IC50 of L(-)Fd4C against the L(-)SddC resistant mutant was at least fifty times lower than that against cell growth in culture. DNA polymerase associated with L(-)SddC resistant virions was also found to be less sensitive than that with wild-type HBV to those L-nucleoside triphosphates. All the L(-)SddC resistant mutants were still sensitive to 9-(2-phosphonylmethoxyethyl)-adenine (PMEA). These results suggest that different mutations in the HBV genome have a different impact on its sensitivity to those compounds, and L(-)SddC resistant HBV may also be resistant to PCV, L-FMAU, and L(-)Fd4C. A nucleoside analogue less toxic than PMEA could be developed against L(-)SddC resistant HBV.
Fu
L
L
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Liu
S H
SH
Cheng
Y C
YC
D000212:Acyclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives / Q000494:pharmacology; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D006147:Guanine; D006515:Hepatitis B virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019259:Lamivudine / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates; D016047:Zalcitabine / Q000031:analogs & derivatives / Q000494:pharmacology
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates; D019259:Lamivudine; D001086:Arabinofuranosyluracil; C053539:penciclovir; D006147:Guanine; C053001:adefovir; D016047:Zalcitabine; D004259:DNA-Directed DNA Polymerase; C034935:clevudine; D000225:Adenine; C099405:dexelvucitabine; D000212:Acyclovir