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In vitro activity of structurally diverse nucleoside analogs against human immunodeficiency virus type 1 with the K65R mutation in reverse transcriptase.

Authors :
Parikh UM
Koontz DL
Chu CK
Schinazi RF
Mellors JW
Source :
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2005 Mar; Vol. 49 (3), pp. 1139-44.
Publication Year :
2005

Abstract

Human immunodeficiency virus type 1 (HIV-1) with a lysine-to-arginine substitution at codon 65 (HIV-1(65R)) 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-1(65R) 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-1(65R) to determine how NRTI structure affects activity. Drug susceptibilities of recombinant wild-type (HIV-1(65K)) or mutant HIV-1(65R) 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-1(65R) than against HIV-1(65K) except for analogs containing a 3'-azido moiety. Pseudosugar structure and base component but not enantiomer influenced NRTI activity against HIV-1(65R). These findings support the inclusion of 3'-azido-3'-deoxythymidine in drug combinations to treat patients having HIV-1(65R) and to prevent its emergence.

Details

Language :
English
ISSN :
0066-4804
Volume :
49
Issue :
3
Database :
MEDLINE
Journal :
Antimicrobial agents and chemotherapy
Publication Type :
Academic Journal
Accession number :
15728915
Full Text :
https://doi.org/10.1128/AAC.49.3.1139-1144.2005