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Antimicrobial Agents and Chemotherapy, November 2006, p. 3867-3874, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00239-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Emergence of a Novel Lamivudine-Resistant Hepatitis B Virus Variant with a Substitution Outside the YMDD Motif{triangledown}

Hiromi Yatsuji,1,2 Chiemi Noguchi,1,2 Nobuhiko Hiraga,1,2 Nami Mori,1,2 Masataka Tsuge,1,2 Michio Imamura,1,2 Shoichi Takahashi,1,2 Eiji Iwao,3 Yoshifumi Fujimoto,2,4 Hidenori Ochi,2,4 Hiromi Abe,1,4 Toshiro Maekawa,4 Chise Tateno,2,5 Katsutoshi Yoshizato,2,5,6 Fumitaka Suzuki,7 Hiromitsu Kumada,7 and Kazuaki Chayama1,2,4*

Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima-shi, 734-8551, Japan,1 Liver Research Project Center, Hiroshima University, Hiroshima, Japan,2 Pharmaceuticals Research Unit, Mitsubishi Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan,3 Laboratory for Liver Disease, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Yokohama 230-0045, Japan,4 Yoshizato Project, CLUSTER, and Hiroshima Prefectural Institute of Industrial Science and Technology, Higashihiroshima, Japan,5 Developmental Biology Laboratory, Department of Biological Science, Graduate School of Science, Hiroshima University, Higashihiroshima, Japan,6 Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan7

Received 24 February 2006/ Returned for modification 21 April 2006/ Accepted 1 September 2006

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.

* Corresponding author. Mailing address: Department of Medical and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Phone: 81-82-257-5190. Fax: 81-82-255-6220. E-mail: chayama{at}hiroshima-u.ac.jp.

{triangledown} Published ahead of print on 18 September 2006.

Antimicrobial Agents and Chemotherapy, November 2006, p. 3867-3874, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00239-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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