Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2001-2-22
pubmed:abstractText
TSAO derivatives represent a class of nonnucleoside reverse transcriptase inhibitors (NNRTIs) that consistently select for the Glu138Lys resistance mutation in HIV-1 reverse transcriptase (RT). Seven RT mutants (i.e., Ala, Asp, Gln, Gly, Lys, Phe, and Tyr) were constructed by site-directed mutagenesis. The mutant Glu138Asp, Glu138Lys, Glu138Gln, Glu138Ala, and Glu138Gly RTs retained marked catalytic activity. In contrast, the Glu138Phe and Glu138Tyr RT mutants showed poor RNA-dependent DNA polymerase activity (30 and 4% of wild-type, respectively). TSAO derivatives lost their inhibitory activity against all mutant enzymes, except against the closely related Glu138Asp RT mutant that remained as sensitive to TSAOs as did wild-type RT. Other NNRTIs, including delavirdine, emivirine, and UC-781, and the NRTI ddGTP retained pronounced inhibitory activity against all mutant enzymes. When the amino acid mutations at position 138 of RT were introduced in recombinant virus clones, the sensitivity/resistance spectrum obtained toward the TSAOs and other NNRTIs was similar to those observed for the isolated recombinant mutant enzymes. The Glu138Lys RT mutant virus had the most marked resistance to TSAOs, followed by the Glu138Gln, Glu138Phe, Glu138Gly, Glu138Tyr, and Glu138Ala virus mutants. The Glu138Asp RT mutant virus kept full sensitivity to the TSAO derivatives. Mixtures of Glu138Lys RT mutant virus with the other virus clones mutated at the 138 position resulted in all cases, except for the Glu138Asp and Glu138Gly RT mutant viruses, in an outgrowth of the Glu138Lys RT mutant virus. Since the Glu138Lys RT proved most resistant to TSAO derivatives, was among the most catalytically efficient enzymes, and resulted in highly replication-competent virus, our data explain why the Glu138Lys RT mutant virus strains but not virus strains containing other amino acids at position 138 invariably emerge in cell cultures under TSAO drug pressure.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/(2',5'-bis-O-(tert-butyldimethylsily..., http://linkedlifedata.com/resource/pubmed/chemical/1-(2',5'-bis-O-(tert-butyldimethylsi..., http://linkedlifedata.com/resource/pubmed/chemical/2',3'-dideoxyguanosine..., http://linkedlifedata.com/resource/pubmed/chemical/Alanine, http://linkedlifedata.com/resource/pubmed/chemical/Anti-HIV Agents, http://linkedlifedata.com/resource/pubmed/chemical/Aspartic Acid, http://linkedlifedata.com/resource/pubmed/chemical/DNA-Directed DNA Polymerase, http://linkedlifedata.com/resource/pubmed/chemical/Deoxyguanine Nucleotides, http://linkedlifedata.com/resource/pubmed/chemical/Dideoxynucleotides, http://linkedlifedata.com/resource/pubmed/chemical/Glutamic Acid, http://linkedlifedata.com/resource/pubmed/chemical/Glutamine, http://linkedlifedata.com/resource/pubmed/chemical/HIV Reverse Transcriptase, http://linkedlifedata.com/resource/pubmed/chemical/Lysine, http://linkedlifedata.com/resource/pubmed/chemical/Nucleosides, http://linkedlifedata.com/resource/pubmed/chemical/Phenylalanine, http://linkedlifedata.com/resource/pubmed/chemical/RNA-Directed DNA Polymerase, http://linkedlifedata.com/resource/pubmed/chemical/Reverse Transcriptase Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Spiro Compounds, http://linkedlifedata.com/resource/pubmed/chemical/Thymidine, http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0042-6822
pubmed:author
pubmed:copyrightInfo
Copyright 2001 Academic Press.
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
97-106
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:11162823-Alanine, pubmed-meshheading:11162823-Anti-HIV Agents, pubmed-meshheading:11162823-Aspartic Acid, pubmed-meshheading:11162823-Cell Line, pubmed-meshheading:11162823-DNA-Directed DNA Polymerase, pubmed-meshheading:11162823-Deoxyguanine Nucleotides, pubmed-meshheading:11162823-Dideoxynucleotides, pubmed-meshheading:11162823-Glutamic Acid, pubmed-meshheading:11162823-Glutamine, pubmed-meshheading:11162823-HIV Reverse Transcriptase, pubmed-meshheading:11162823-HIV-1, pubmed-meshheading:11162823-Humans, pubmed-meshheading:11162823-Lysine, pubmed-meshheading:11162823-Mutagenesis, Site-Directed, pubmed-meshheading:11162823-Nucleosides, pubmed-meshheading:11162823-Phenylalanine, pubmed-meshheading:11162823-RNA-Directed DNA Polymerase, pubmed-meshheading:11162823-Recombination, Genetic, pubmed-meshheading:11162823-Reverse Transcriptase Inhibitors, pubmed-meshheading:11162823-Spiro Compounds, pubmed-meshheading:11162823-Thymidine, pubmed-meshheading:11162823-Tyrosine
pubmed:year
2001
pubmed:articleTitle
Site-directed mutagenesis of human immunodeficiency virus type 1 reverse transcriptase at amino acid position 138.
pubmed:affiliation
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, B-3000, Belgium.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't