Viral Evolution in Response to the Broad-Based Retroviral Protease Inhibitor TL-3
| Autor: | Arthur J. Olson, Bernd Bühler, Chi-Huey Wong, John H. Elder, Garrett M. Morris, Ying-Chuan Lin, Bruce E. Torbett, Douglas D. Richman |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Feline immunodeficiency virus
medicine.medical_treatment Molecular Sequence Data Immunology Genome Viral Biology Microbiology Virus Evolution Molecular Virology Vaccines and Antiviral Agents medicine Animals Humans Protease Inhibitors Protease inhibitor (pharmacology) Amino Acid Sequence chemistry.chemical_classification NS3 Protease biology.organism_classification Molecular biology NS2-3 protease Retroviridae Enzyme chemistry Insect Science Cats MASP1 |
| Zdroj: | Journal of Virology. 75:9502-9508 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.75.19.9502-9508.2001 |
| Popis: | TL-3 is a protease inhibitor developed using the feline immunodeficiency virus protease as a model. It has been shown to efficiently inhibit replication of human, simian, and feline immunodeficiency viruses and therefore has broad-based activity. We now demonstrate that TL-3 efficiently inhibits the replication of 6 of 12 isolates with confirmed resistance mutations to known protease inhibitors. To dissect the spectrum of molecular changes in protease and viral properties associated with resistance to TL-3, a panel of chronological in vitro escape variants was generated. We have virologically and biochemically characterized mutants with one (V82A), three (M46I/F53L/V82A), or six (L24I/M46I/F53L/L63P/V77I/V82A) changes in the protease and structurally modeled the protease mutant containing six changes. Virus containing six changes was found to be 17-fold more resistant to TL-3 in cell culture than was wild-type virus but maintained similar in vitro replication kinetics compared to the wild-type virus. Analyses of enzyme activity of protease variants with one, three, and six changes indicated that these enzymes, compared to wild-type protease, retained 40, 47, and 61% activity, respectively. These results suggest that deficient protease enzymatic activity is sufficient for function, and the observed protease restoration might imply a selective advantage, at least in vitro, for increased protease activity. |
| Databáze: | OpenAIRE |
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