Open AccessAmino 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
Author(s) -
Atsuko Hachiya,
Eiichi Kodama,
Stefan G. Sarafianos,
Matthew M. Schuckmann,
Yasuko Sakagami,
Masao Matsuoka,
Masafumi Takiguchi,
Hiroyuki Gatanaga,
Shinichi Oka
Publication year - 2008
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.01154-07
Subject(s) - reverse transcriptase , biology , resistance mutation , virology , zidovudine , didanosine , nevirapine , nucleotidyltransferase , nucleoside reverse transcriptase inhibitor , reverse transcriptase inhibitor , mutation , virus , microbiology and biotechnology , genetics , rna , viral disease , viral load , sida , gene , antiretroviral therapy
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.