Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74-->Val or Ile and Val-75-->Leu or Ile) HIV-1 mutants
| Autoři: | Y. Hsiou, Reinhard Kirsch, Irvin Winkler, Gunther Riess, Manfred Rösner, Edward Arnold, Arno Paessens, Jorg-Peter Kleim |
|---|---|
| Zdroj: | Proceedings of the National Academy of Sciences. 93:34-38 |
| Informace o vydavateli: | Proceedings of the National Academy of Sciences, 1996. |
| Rok vydání: | 1996 |
| Témata: | Mutation, Multidisciplinary, Mutant, Stavudine, Biology, medicine.disease_cause, Virology, Molecular biology, Reverse transcriptase, Virus, Dideoxyadenosine, Viral replication, medicine, Didanosine, medicine.drug |
| Popis: | The quinoxaline nonnucleoside RT inhibitor (NNRTI) (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4- dihydroquinoxaline-2(1H)-thione (HBY 097) was used to select for drug-resistant HIV-1 variants in vitro. The viruses first developed mutations affecting the NNRTI-binding pocket, and five of six strains displayed the RT G190-->E substitution, which is characteristic for HIV-1 resistance against quinoxalines. In one variant, a new mutant (G190-->Q) most likely evolved from preexisting G190-->E mutants. The negative charge introduced by the G190-->E substitution was maintained at that site of the pocket by simultaneous selection for V179-->D together with G190-->Q. After continued exposure to the drug, mutations at positions so far known to be specific for resistance against nucleoside RT inhibitors (NRTIs) (L74-->V/I and V75-->L/I) were consistently detected in all cultures. The inhibitory activities of the cellular conversion product of 2',3'-dideoxyinosine (ddI, didanosine), 2',3'-dideoxyadenosine (ddA) and of 2',3'-didehydro-3'-deoxythymidine (d4T, stavudine) against these late-passage viruses were shown to be enhanced with the L74-->V/I RT mutant virus as compared with the wild-type (wt) HIV-1MN isolate. Clonal analysis proved linkage of the codon 74 and codon 75 mutations to the NNRTI-specific mutations in all RT gene fragments. The nonnucleoside- and nucleoside-resistance mutation sites are separated by approximately 35 A. We propose that the two sites "communicate" through the template-primer which is situated in the DNA-binding cleft between these two sites. Quinoxalines cause high selective pressure on HIV-1 replication in vitro; however, the implication of these findings for the treatment of HIV-1 infection has yet to be determined. |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.93.1.34 |
| Přístupová URL adresa: | https://explore.openaire.eu/search/publication?articleId=doi_________::cdd7089bd332ff10f9b78508a768626d https://doi.org/10.1073/pnas.93.1.34 |
| Rights: | OPEN |
| Přírůstkové číslo: | edsair.doi...........cdd7089bd332ff10f9b78508a768626d |
| Autor: | Y. Hsiou, Reinhard Kirsch, Irvin Winkler, Gunther Riess, Manfred Rösner, Edward Arnold, Arno Paessens, Jorg-Peter Kleim |
| Rok vydání: | 1996 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences. 93:34-38 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.93.1.34 |
| Popis: | The quinoxaline nonnucleoside RT inhibitor (NNRTI) (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4- dihydroquinoxaline-2(1H)-thione (HBY 097) was used to select for drug-resistant HIV-1 variants in vitro. The viruses first developed mutations affecting the NNRTI-binding pocket, and five of six strains displayed the RT G190-->E substitution, which is characteristic for HIV-1 resistance against quinoxalines. In one variant, a new mutant (G190-->Q) most likely evolved from preexisting G190-->E mutants. The negative charge introduced by the G190-->E substitution was maintained at that site of the pocket by simultaneous selection for V179-->D together with G190-->Q. After continued exposure to the drug, mutations at positions so far known to be specific for resistance against nucleoside RT inhibitors (NRTIs) (L74-->V/I and V75-->L/I) were consistently detected in all cultures. The inhibitory activities of the cellular conversion product of 2',3'-dideoxyinosine (ddI, didanosine), 2',3'-dideoxyadenosine (ddA) and of 2',3'-didehydro-3'-deoxythymidine (d4T, stavudine) against these late-passage viruses were shown to be enhanced with the L74-->V/I RT mutant virus as compared with the wild-type (wt) HIV-1MN isolate. Clonal analysis proved linkage of the codon 74 and codon 75 mutations to the NNRTI-specific mutations in all RT gene fragments. The nonnucleoside- and nucleoside-resistance mutation sites are separated by approximately 35 A. We propose that the two sites "communicate" through the template-primer which is situated in the DNA-binding cleft between these two sites. Quinoxalines cause high selective pressure on HIV-1 replication in vitro; however, the implication of these findings for the treatment of HIV-1 infection has yet to be determined. |
| Databáze: | OpenAIRE |
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