In Vitro Activity of Structurally Diverse Nucleoside Analogs against Human Immunodeficiency Virus Type 1 with the K65R Mutation in Reverse Transcriptase

AUTOR(ES)

Parikh, Urvi M.

FONTE

American Society for Microbiology

RESUMO

Human immunodeficiency virus type 1 (HIV-1) with a lysine-to-arginine substitution at codon 65 (HIV-165R) of reverse transcriptase (RT) can rapidly emerge in patients being treated with specific combinations of nucleoside analog RT inhibitors (NRTIs). A better understanding of the activity of approved and investigational NRTIs against HIV-165R is needed to select optimal therapy for patients infected with this mutant and to devise strategies to prevent its emergence. Therefore, we tested a broad panel of NRTIs that differed by enantiomer, pseudosugar, and base component against HIV-165R to determine how NRTI structure affects activity. Drug susceptibilities of recombinant wild-type (HIV-165K) or mutant HIV-165R were determined using a single-replication-cycle susceptibility assay with P4/R5 cells and/or a multiple-replication-cycle susceptibility assay with MT-2 cells. All d, l, and acyclic NRTIs were significantly less active against HIV-165R than against HIV-165K except for analogs containing a 3′-azido moiety. Pseudosugar structure and base component but not enantiomer influenced NRTI activity against HIV-165R. These findings support the inclusion of 3′-azido-3′-deoxythymidine in drug combinations to treat patients having HIV-165R and to prevent its emergence.

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