Combination of mutations in human immunodeficiency virus type 1 reverse transcriptase required for resistance to the carbocyclic nucleoside 1592U89
- 1 May 1997
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 41 (5), 1094-1098
- https://doi.org/10.1128/aac.41.5.1094
Abstract
The carbocyclic nucleoside 1592U89 is a selective inhibitor of the human immunodeficiency virus (HIV), targeting the reverse transcriptase (RT). In vitro selection studies were undertaken to generate resistant variants with both HIV type 1 (HIV-1) wild-type strain HIV-1(HXB2) and 39-azido-39-deoxythymidine (AZT)-resistant strain HIV-1(RTMC). At least two or three mutations in RT were required to produce a 10-fold reduction in susceptibility. The first RT mutation selected was at codon 184, methionine (M) to valine (V), for HIV-1(HXB2) and HIV-1(RTMC), conferring two- and fivefold resistance, respectively. Two additional mutations were selected with HIV-1(HXB2), either leucine (L) 74 to V and lysine (K) 65 to arginine (R) (first-passage series) or L74 to V and tyrosine (Y) 115 to phenylalanine (F) (second-passage series). Cloned variants, obtained from the 1592U89 selection, were either double RT mutants 65R/184V and 74V/184V or triple RT mutant 74V/115Y/184V. Molecular clones were constructed with single, double, and triple combinations of these mutations for resistance analysis with different RT inhibitors. Each individual mutation conferred only low-level resistance (two- to fourfold) to 1592U89 in the HXB2 background. Double mutants containing the 184V mutation and triple mutants showed slightly greater levels of resistance to 1592U89 (7- to 11-fold). Some of the 1592U89-resistant variants were cross-resistant with 29,39-dideoxycytidine, 29,39-dideoxyinosine, and (-)-29-deoxy-39-thiacytidine, but none were resistant to 29,39-didehydro-39-deoxythymidine or AZT.Keywords
This publication has 24 references indexed in Scilit:
- High resolution structures of HIV-1 RT from four RT–inhibitor complexesNature Structural & Molecular Biology, 1995
- Combination Therapy with Zidovudine and Didanosine Selects for Drug-Resistant Human Immunodeficiency Virus Type 1 Strains with Unique Patterns of pol Gene MutationsThe Journal of Infectious Diseases, 1994
- Resistance to 2',3'-dideoxycytidine conferred by a mutation in codon 65 of the human immunodeficiency virus type 1 reverse transcriptaseAntimicrobial Agents and Chemotherapy, 1994
- Identification of a mutation at codon 65 in the IKKK motif of reverse transcriptase that encodes human immunodeficiency virus resistance to 2',3'-dideoxycytidine and 2',3'-dideoxy-3'-thiacytidineAntimicrobial Agents and Chemotherapy, 1994
- Recombinant virus assay: a rapid, phenotypic assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolatesAntimicrobial Agents and Chemotherapy, 1994
- Resistance to ddI and Sensitivity to AZT Induced by a Mutation in HIV-1 Reverse TranscriptaseScience, 1991
- Zidovudine resistance predicted by direct detection of mutations in DNA from HIV-infected lymphocytesAIDS, 1991
- HIV with Reduced Sensitivity to Zidovudine (AZT) Isolated During Prolonged TherapyScience, 1989
- A molecular clone of HTLV-III with biological activityNature, 1985
- Nonrandomness of point mutation as reflected in nucleotide substitutions in pseudogenes and its evolutionary implicationsJournal of Molecular Evolution, 1984