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Emergence of a novel lamivudine-resistant hepatitis B virus variant with a substitution outside the YMDD motif.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Yatsuji, Hiromi Noguchi, Chiemi Hiraga, Nobuhiko Mori, Nami Tsuge, Masataka Imamura, Michio Takahashi, Shoichi Iwao, Eiji Fujimoto, Yoshifumi Ochi, Hidenori Abe, Hiromi Maekawa, Toshiro Tateno, Chise Yoshizato, Katsutoshi Suzuki, Fumitaka Kumada, Hiromitsu Chayama, Kazuaki |
| Copyright Year | 2006 |
| Abstract | Lamivudine is a major drug approved for treatment of chronic hepatitis B virus (HBV) infection. Emergence of drug-resistant mutants with amino acid substitutions in the YMDD motif is a well-documented problem during long-term lamivudine therapy. Here we report a novel lamivudine-resistant strain of HBV with an intact YMDD motif, which included an amino acid substitution, rtA181T, in the reverse transcriptase (RT) domain of HBV polymerase. The substitution also induced a unique amino acid substitution (W172L) in the overlapping hepatitis B surface (HBs) protein. The YMDD mutant strains were not detected even by using the sensitive peptide nucleic acid-mediated PCR clamping method. The detected nucleotide substitution was accompanied by the emergence of an additional nucleotide substitution that induced amino acid change (S331C) in the spacer domain. The rtA181T mutant strain displayed a threefold decrease in susceptibility to lamivudine in in vitro experiments in comparison with the wild type. In vivo analysis using human hepatocyte-chimeric mice confirmed the resistance of this mutant strain to lamivudine. We developed a method to detect this novel rtA181T mutation and a previously reported rtA181T mutation with the HBs stop codon using restriction fragment length polymorphism PCR and identified one patient with the latter pattern among 40 patients with lamivudine resistance. In conclusion, although the incidence is not high, we have to be careful regarding the emergence of lamivudine-resistant mutant strains with intact YMDD motif. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://aac.asm.org/content/50/11/3867.full.pdf |
| Alternate Webpage(s) | http://aac.asm.org/content/early/2006/09/18/AAC.00239-06.full.pdf |
| PubMed reference number | 16982790v1 |
| Volume Number | 50 |
| Issue Number | 11 |
| Journal | Antimicrobial agents and chemotherapy |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Amino Acid Substitution Amino Acids Chemical and Drug Induced Liver Injury Chimera organism Codon, Terminator Glucose Clamping Hepatitis B Surface Antigens Hepatitis B Virus Hepatitis B, Chronic Hepatitis, Chronic Hepatocyte Herpesvirus 1, Cercopithecine In Vitro [Publication Type] Lamivudine Mutation Nucleotides Patients Peptide Nucleic Acids Protein Domain RNA-Directed DNA Polymerase Spacer Device Component Wild Type |
| Content Type | Text |
| Resource Type | Article |
