In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-1) isolates with reduced sensitivity to hydroxyethylamino sulfonamide inhibitors of HIV-1 aspartyl protease
| Jazyk: | English |
|---|---|
| Přístupová URL adresa: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a15bb42c43e9463a0baffaa0308e0dea https://europepmc.org/articles/PMC189353/ |
| Rights: | OPEN |
| Přírůstkové číslo: | edsair.doi.dedup.....a15bb42c43e9463a0baffaa0308e0dea |
| Autor: | O Futer, E E Blair, A B Cullinan, J. A. Partaledis, R E Myers, K Yamaguchi, B Maschera, C Falcione, S. Pazhanisamy, M. Tisdale |
| Jazyk: | angličtina |
| Rok vydání: | 1995 |
| Předmět: |
Models
Molecular Protein Conformation medicine.medical_treatment T-Lymphocytes Immunology Mutant Molecular Sequence Data Microbial Sensitivity Tests Biology medicine.disease_cause Virus Replication Microbiology Polymerase Chain Reaction Virus Cell Line Structure-Activity Relationship HIV Protease Serial passage Virology medicine HIV Protease Inhibitor Humans Point Mutation Amino Acid Sequence Furans DNA Primers chemistry.chemical_classification Mutation Sulfonamides Protease Base Sequence Molecular Structure Point mutation HIV Protease Inhibitors Molecular biology Recombinant Proteins Kinetics Enzyme chemistry Insect Science HIV-1 Mutagenesis Site-Directed Carbamates Research Article |
| Popis: | Human immunodeficiency virus type 1 (HIV-1) variants with reduced sensitivity to the hydroxyethylamino sulfonamide protease inhibitors VB-11,328 and VX-478 have been selected in vitro by two independent serial passage protocols with HIV-1 in CEM-SS and MT-4 cell lines. Virus populations with greater than 100-fold-increased resistance to both inhibitors compared with the parental virus have been obtained. DNA sequence analyses of the protease genes from VB-11,328- and VX-478-resistant variants reveal a sequential accumulation of point mutations, with similar resistance patterns occurring for the two inhibitors. The deduced amino acid substitutions in the resistant protease are Leu-10-->Phe, Met-46-->Ile, Ile-47-->Val, and Ile-50-->Val. This is the first observation in HIV protease resistance studies of an Ile-50-->Val mutation, a mutation that appears to arise uniquely against the sulfonamide inhibitor class. When the substitutions observed were introduced as single mutations into an HIV-1 infectious clone (HXB2), only the Ile-50-->Val mutant showed reduced sensitivity (two- to threefold) to VB-11,328 and VX-478. A triple protease mutant infectious clone carrying the mutations Met-46-->Ile, Ile-47-->Val, and Ile-50-->Val, however, showed much greater reduction in sensitivity (14- to 20-fold) to VB-11,328 and VX-478. The same mutations were studied in recombinant HIV protease. The mutant protease Ile-50-->Val displays a much lower affinity for the inhibitors than the parent enzyme (< or = 80-fold). The protease triply mutated at Met-46-->Ile, Ile-47-->Val, and Ile-50-->Val shows an even greater decrease in inhibitor binding (< or = 270-fold). The sulfonamide-resistant HIV protease variants remain sensitive to inhibitors from other chemical classes (Ro 31-8959 and L-735,524), suggesting possibilities for clinical use of HIV protease inhibitors in combination or serially. |
| Databáze: | OpenAIRE |
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