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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
2007-4-23
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pubmed:abstractText |
Several rare and novel NNRTI [non-nucleoside reverse transcriptase (RT) inhibitor] resistance mutations were recently detected at codons 132 and 135 in RTs from clinical isolates using the yeast-based chimaeric TyHRT (Ty1/HIV-1 RT) phenotypic assay. Ile132 and Ile135 form part of the beta7-beta8 loop of HIV-1 RT (residues 132-140). To elucidate the contribution of these residues in RT structure-function and drug resistance, we constructed twelve recombinant enzymes harbouring mutations at codons 132 and 135-140. Several of the mutant enzymes exhibited reduced DNA polymerase activities. Using the yeast two-hybrid assay for HIV-1 RT dimerization we show that in some instances this decrease in enzyme activity could be attributed to the mutations, in the context of the 51 kDa subunit of HIV-1 RT, disrupting the subunit-subunit interactions of the enzyme. Drug resistance analyses using purified RT, the TyHRT assay and antiviral assays demonstrated that the I132M mutation conferred high-level resistance (>10-fold) to nevirapine and delavirdine and low-level resistance (approximately 2-3-fold) to efavirenz. The I135A and I135M mutations also conferred low level NNRTI resistance (approximately 2-fold). Subunit selective mutagenesis studies again demonstrated that resistance was conferred via the p51 subunit of HIV-1 RT. Taken together, our results highlight a specific role of residues 132 and 135 in NNRTI resistance and a general role for residues in the beta7-beta8 loop in the stability of HIV-1 RT.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-10103027,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-10841542,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-11044070,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-11583149,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-1377403,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-15113918,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-15564466,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-15833734,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-15848161,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-15852304,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-15942890,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-15961674,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-15980332,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-16189079,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-16251284,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-16272507,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-16472877,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-16611119,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-16825395,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-1688798,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-16911530,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-1693146,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-1718777,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-7517553,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-8594344,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-8598898,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-9420060,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-9754886,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-9765485,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17286555-9811899
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1470-8728
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
404
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
151-7
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:17286555-Circular Dichroism,
pubmed-meshheading:17286555-Cloning, Molecular,
pubmed-meshheading:17286555-DNA, Viral,
pubmed-meshheading:17286555-HIV Reverse Transcriptase,
pubmed-meshheading:17286555-HIV-1,
pubmed-meshheading:17286555-Models, Molecular,
pubmed-meshheading:17286555-Molecular Conformation,
pubmed-meshheading:17286555-Protein Conformation,
pubmed-meshheading:17286555-Protein Subunits,
pubmed-meshheading:17286555-RNA, Viral,
pubmed-meshheading:17286555-Recombinant Proteins,
pubmed-meshheading:17286555-Reverse Transcriptase Inhibitors,
pubmed-meshheading:17286555-Saccharomyces cerevisiae
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pubmed:year |
2007
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pubmed:articleTitle |
Characterization of novel non-nucleoside reverse transcriptase (RT) inhibitor resistance mutations at residues 132 and 135 in the 51 kDa subunit of HIV-1 RT.
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pubmed:affiliation |
Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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