title: Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors.
abstract: The nonnucleoside reverse transcriptase (RT) inhibitors comprise a class of structurally diverse compounds that are functionally related and specific for the human immunodeficiency virus type 1 RT. Viral variants resistant to these compounds arise readily in cell culture and in treated, infected human. Therefore, the eventual clinical usefulness of the nonnucleoside inhibitors will rely on a thorough understanding of the genetic and biochemical bases for resistance. A study was performed to assess the effects of substitutions at each RT amino acid residue that influences the enzyme's susceptibility to the various nonnucleoside compounds. Single substitutions were introduced into both purified enzyme and virus. The resulting patterns of resistance were markedly distinct for each of the tested inhibitors. For instance, a > 50-fold loss of enzyme susceptibility to BI-RG-587 was engendered by any of four individual substitutions, while the same level of relative resistance to the pyridinone derivatives was mediated only by substitution at residue 181. Similarly, substitution at residue 181. Similarly, substitution at residue 106 had a noted effect on virus resistance to BI-RG-587 but not to the pyridinones. The opposite effect was mediated by a substitution at residue 179. Such knowledge of nonucleoside inhibitor resistance profiles may help in understanding the basis for resistant virus selection during clinical studies of these compounds.
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: V W
authors.initials: VW
authors.lastname: Byrnes
authors.forename: V V
authors.initials: VV
authors.lastname: Sardana
authors.forename: W A
authors.initials: WA
authors.lastname: Schleif
authors.forename: J H
authors.initials: JH
authors.lastname: Condra
authors.forename: J A
authors.initials: JA
authors.lastname: Waterbury
authors.forename: J A
authors.initials: JA
authors.lastname: Wolfgang
authors.forename: W J
authors.initials: WJ
authors.lastname: Long
authors.forename: C L
authors.initials: CL
authors.lastname: Schneider
authors.forename: A J
authors.initials: AJ
authors.lastname: Schlabach
authors.forename: B S
authors.initials: BS
authors.lastname: Wolanski
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001583:Benzoxazoles / Q000627:therapeutic use; D004279:DNA, Viral / Q000235:genetics; D014644:Genetic Variation; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009705:Nucleosides / Q000494:pharmacology*; D011728:Pyridones / Q000627:therapeutic use; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D001583:Benzoxazoles; D004279:DNA, Viral; D009705:Nucleosides; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; C076516:L-697661; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase