title: 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.
abstract: 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.
authors.affiliation: Laboratory of Virus Immunology, Research Center for AIDS, Institute for Virus Research, Kyoto University, 53, Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hachiya
authors.forename: Eiichi N
authors.initials: EN
authors.lastname: Kodama
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Sarafianos
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Schuckmann
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Sakagami
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics*; D015658:HIV Infections / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D019829:Nevirapine / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D014779:Virus Replication / Q000235:genetics
chemical_list: D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase