Mutational Analysis of Residue 190 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase

S-2720 and other members of the quinoline/quinoxaline class of HIV-1-specific nonnucleoside reverse transcriptase inhibitors (NNRTIs) select for a glycine to glutamate substitution at residue 190 (Gly 190 Glu) of the reverse transcriptace (RT), when drug-resistant viruses are generated in cell cultu...

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Veröffentlicht in:Virology (New York, N.Y.) N.Y.), 1994-05, Vol.200 (2), p.696-701
Hauptverfasser: Kleim, Jörg-Peter, Bender, Rudolf, Kirsch, Reinhard, Meichsner, Christoph, Paessens, Arno, Rieb, Günther
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container_issue 2
container_start_page 696
container_title Virology (New York, N.Y.)
container_volume 200
creator Kleim, Jörg-Peter
Bender, Rudolf
Kirsch, Reinhard
Meichsner, Christoph
Paessens, Arno
Rieb, Günther
description S-2720 and other members of the quinoline/quinoxaline class of HIV-1-specific nonnucleoside reverse transcriptase inhibitors (NNRTIs) select for a glycine to glutamate substitution at residue 190 (Gly 190 Glu) of the reverse transcriptace (RT), when drug-resistant viruses are generated in cell culture. This mutation has not been described to appear upon selection for resistant viral variants using derivatives of any other class of NNRTIs. Notably, the RNA-dependent DNA polymerase activity of the Gly 190 Glu mutant enzyme is drastically diminished with respect to the wild-type RT. We describe here the effects of other amino acid substitutions at position 190 of the RT that were introduced by using site-directed mutagenesis. Polymerase activities and sensitivities to inhibition by a number of NNRTIs were determined for the different RT mutants. In general, an inverse correlation was found between the enzymatic activity and increasing length of the side chain, whereas the size of the residue and the level of resistance to NNRTIs appeared to be positively related. Double mutants, which contain the Gly 190 Glu mutation together with substitutions that confer resistance to other RT inhibitors, were all shown to possess severely diminished polymerase activity.
doi_str_mv 10.1006/viro.1994.1233
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source MEDLINE; Access via ScienceDirect (Elsevier); EZB-FREE-00999 freely available EZB journals
subjects Antiviral Agents - pharmacology
Base Sequence
Benzodiazepines - pharmacology
Benzoxazoles - pharmacology
Biological and medical sciences
Delavirdine
DNA Mutational Analysis
Drug Resistance, Microbial - genetics
Fundamental and applied biological sciences. Psychology
Genetics
HIV Reverse Transcriptase
HIV-1 - enzymology
HIV-1 - genetics
human immunodeficiency virus 1
Imidazoles - pharmacology
Indoles - pharmacology
Microbiology
Molecular Sequence Data
Mutagenesis, Site-Directed
Nevirapine
Piperazines - pharmacology
Pyridines - pharmacology
Pyridones - pharmacology
Quinoxalines - pharmacology
Reverse Transcriptase Inhibitors
RNA-Directed DNA Polymerase - drug effects
RNA-Directed DNA Polymerase - genetics
Selection, Genetic
Structure-Activity Relationship
Virology
title Mutational Analysis of Residue 190 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase
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