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Journal of Virology, April 2008, p. 3261-3270, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01154-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Amino Acid Mutation N348I in the Connection Subdomain of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confers Multiclass Resistance to Nucleoside and Nonnucleoside Reverse Transcriptase Inhibitors{triangledown} ,{dagger}

Atsuko Hachiya,1,2 Eiichi N. Kodama,3* Stefan G. Sarafianos,4 Matthew M. Schuckmann,4 Yasuko Sakagami,3 Masao Matsuoka,3 Masafumi Takiguchi,2 Hiroyuki Gatanaga,1 and Shinichi Oka1

AIDS Clinical Center, International Medical Center of Japan, Tokyo, Japan,1 Center for AIDS Research, Kumamoto University, Kumamoto, Japan,2 Institute for Virus Research, Kyoto University, Kyoto, Japan,3 Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Bond Life Sciences Center, Columbia, Missouri4

Received 28 May 2007/ Accepted 9 January 2008

We identified clinical isolates with phenotypic resistance to nevirapine (NVP) in the absence of known nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations. This resistance is caused by N348I, a mutation at the connection subdomain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Virologic analysis showed that N348I conferred multiclass resistance to NNRTIs (NVP and delavirdine) and to nucleoside reverse transcriptase inhibitors (zidovudine [AZT] and didanosine [ddI]). N348I impaired HIV-1 replication in a cell-type-dependent manner. Acquisition of N348I was frequently observed in AZT- and/or ddI-containing therapy (12.5%; n = 48; P < 0.0001) and was accompanied with thymidine analogue-associated mutations, e.g., T215Y (n = 5/6) and the lamivudine resistance mutation M184V (n = 1/6) in a Japanese cohort. Molecular modeling analysis shows that residue 348 is proximal to the NNRTI-binding pocket and to a flexible hinge region at the base of the p66 thumb that may be affected by the N348I mutation. Our results further highlight the role of connection subdomain residues in drug resistance.

* Corresponding author. Mailing address: Laboratory of Virus Immunology, Research Center for AIDS, Institute for Virus Research, Kyoto University, 53, Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Phone and fax: 81 75 751 3986. E-mail: ekodama{at}virus.kyoto-u.ac.jp

{triangledown} Published ahead of print on 23 January 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, April 2008, p. 3261-3270, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01154-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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