title: Broad nucleoside-analogue resistance implications for human immunodeficiency virus type 1 reverse-transcriptase mutations at codons 44 and 118.
abstract: Two large, independent human immunodeficiency virus type 1 resistance databases containing >7700 reverse-transcriptase (RT) sequences were used to analyze the epidemiology of amino acid substitutions at codons 44 and 118, which confer moderate lamivudine resistance in the presence of zidovudine resistance. As expected, E44A/D and V118I mutations were strongly associated with M41L, D67N, L210W, and T215Y but also with other mutations, including K43E/N/Q, T69D, V75M, H208Y, R211K, and K219R. Both E44D and V118I were more frequently associated with stavudine and didanosine than with zidovudine and lamivudine treatment. However, selection of E44A/D and V118I was also detected in association with a switch to other nucleoside RT inhibitors, including zalcitabine and abacavir. Site-directed mutagenesis confirmed that 44D and 118I can decrease phenotypic susceptibility not only to lamivudine but also to most other nucleoside analogues, particularly stavudine and abacavir. Thus, substitutions at RT codons 44 and 118 have broad implications in nucleoside RT inhibitor resistance in the setting of several nucleoside-associated mutations.
authors.affiliation: Sezione di Microbiologia, Dipartimento di Biologia Molecolare, Università di Siena, Siena, Italy. romanol@unisi.it
authors.forename: Laura
authors.initials: L
authors.lastname: Romano
authors.forename: Giulietta
authors.initials: G
authors.lastname: Venturi
authors.forename: Stuart
authors.initials: S
authors.lastname: Bloor
authors.forename: Richard
authors.initials: R
authors.lastname: Harrigan
authors.forename: Brendan A
authors.initials: BA
authors.lastname: Larder
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Major
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zazzi
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D003062:Codon / Q000235:genetics*; D024921:Drug Resistance, Multiple, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D003062:Codon; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase