A family of insertion mutations between codons 67 and 70 of human immunodeficiency virus type 1 reverse transcriptase confer multinucleoside analog resistance.

摘要: To investigate the occurrence of multinucleoside analog resistance during therapy failure, we surveyed drug susceptibilities and genotypes nearly 900 human immunodeficiency virus type 1 (HIV-1) samples. For 302 these, 50% inhibitory concentrations at least four approved nucleoside analogs had fourfold-or-greater increases. Genotypic analysis reverse transcriptase (RT)-coding regions from these samples revealed complex mutational patterns, including previously recognized codon 151 multidrug cluster. Surprisingly, high-level was associated with a diverse family amino acid insertions in addition to “conventional” point mutations. These were found between RT codons 67 70 commonly 69Ser-(Ser-Ser) or 69Ser-(Ser-Gly). Treatment history information showed that common factor for development variants AZT (3′-azido-3′-deoxythymidine, zidovudine) combination 2′,3′-dideoxyinosine 2′,3′-dideoxycytidine, although treatment patterns varied considerably. Site-directed mutagenesis studies confirmed an background conferred simultaneous multiple analogs. The are located “fingers” domain RT. Modelling insertion into structure demonstrated profound direct effect this change is likely have triphosphate binding site enzyme. Our data highlight increasing problem HIV-1 underline importance continued surveillance appropriate, sufficiently versatile genotyping technology phenotypic susceptibility analysis.