Characteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1.
Treatment of human immunodeficiency virus type 1 (HIV-1)-infected CEM cell cultures with escalating concentrations of the quinoxaline S-2720 resulted in an ordered appearance of single and multiple mutant virus strains that gradually became resistant to the quinoxaline and other nonnucleoside revers...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Jezik: | English |
| Izdano: |
1997
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| _version_ | 1826291240462712832 |
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| author | Pelemans, H Esnouf, R Dunkler, A Parniak, M Vandamme, A Karlsson, A De Clercq, E Kleim, J Balzarini, J |
| author_facet | Pelemans, H Esnouf, R Dunkler, A Parniak, M Vandamme, A Karlsson, A De Clercq, E Kleim, J Balzarini, J |
| author_sort | Pelemans, H |
| collection | OXFORD |
| description | Treatment of human immunodeficiency virus type 1 (HIV-1)-infected CEM cell cultures with escalating concentrations of the quinoxaline S-2720 resulted in an ordered appearance of single and multiple mutant virus strains that gradually became resistant to the quinoxaline and other nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs). A novel mutation, Pro225His, consistently appeared in a Val106Ala RT-mutated genetic background. The contribution of this mutation to the resistance of the mutant HIV-1 RT to NNRTIs was additive to the resistance caused by the Val106Ala mutation. Interestingly, site-directed mutagenesis studies revealed that the Pro225His-mutated RT had acquired markedly greater sensitivity to bis(heteroaryl)piperazine (BHAP U-90152) (delavirdine) but not to any of the other NNRTIs. The kinetics of inhibition of the Pro225His mutant RT by the NNRTIs (including BHAP U-90152) was not substantially different from that observed for the wild-type RT. The hypersensitivity of the mutant enzyme and virus to BHAP U-90152 could be rationally explained by the molecular-structural determinants of the RT-BHAP complex, which has recently been resolved by X-ray crystallography. |
| first_indexed | 2024-03-07T02:56:27Z |
| format | Journal article |
| id | oxford-uuid:af72c09f-f42d-4218-b3d0-a78296b83cf1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:56:27Z |
| publishDate | 1997 |
| record_format | dspace |
| spelling | oxford-uuid:af72c09f-f42d-4218-b3d0-a78296b83cf12022-03-27T03:49:39ZCharacteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:af72c09f-f42d-4218-b3d0-a78296b83cf1EnglishSymplectic Elements at Oxford1997Pelemans, HEsnouf, RDunkler, AParniak, MVandamme, AKarlsson, ADe Clercq, EKleim, JBalzarini, JTreatment of human immunodeficiency virus type 1 (HIV-1)-infected CEM cell cultures with escalating concentrations of the quinoxaline S-2720 resulted in an ordered appearance of single and multiple mutant virus strains that gradually became resistant to the quinoxaline and other nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs). A novel mutation, Pro225His, consistently appeared in a Val106Ala RT-mutated genetic background. The contribution of this mutation to the resistance of the mutant HIV-1 RT to NNRTIs was additive to the resistance caused by the Val106Ala mutation. Interestingly, site-directed mutagenesis studies revealed that the Pro225His-mutated RT had acquired markedly greater sensitivity to bis(heteroaryl)piperazine (BHAP U-90152) (delavirdine) but not to any of the other NNRTIs. The kinetics of inhibition of the Pro225His mutant RT by the NNRTIs (including BHAP U-90152) was not substantially different from that observed for the wild-type RT. The hypersensitivity of the mutant enzyme and virus to BHAP U-90152 could be rationally explained by the molecular-structural determinants of the RT-BHAP complex, which has recently been resolved by X-ray crystallography. |
| spellingShingle | Pelemans, H Esnouf, R Dunkler, A Parniak, M Vandamme, A Karlsson, A De Clercq, E Kleim, J Balzarini, J Characteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1. |
| title | Characteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1. |
| title_full | Characteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1. |
| title_fullStr | Characteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1. |
| title_full_unstemmed | Characteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1. |
| title_short | Characteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1. |
| title_sort | characteristics of the pro225his mutation in human immunodeficiency virus type 1 hiv 1 reverse transcriptase that appears under selective pressure of dose escalating quinoxaline treatment of hiv 1 |
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