title: Tissue culture drug resistance analysis of a novel HIV-1 protease inhibitor termed PL-100 in non-B HIV-1 subtypes.
abstract: PL-100 is a novel HIV-1 protease inhibitor (PI) that maintains activity against viruses that are resistant to other PIs. To further characterize this compound, we used it to select for drug resistance in tissue culture, using two non-B HIV-1 subtypes, viz. subtype C and a CRF01_AE recombinant virus. PL-100 selected for both minor and major PI resistance mutations along either of two distinct pathways. One of these involved the V82A and L90M resistance mutations while the other involved a mutation at position T80I, with other mutations being observed at positions M46I/L, I54M, K55R, L76F, P81S and I85V. The resistance patterns in both subtype C and CRF01_AE were similar and an accumulation of at least three mutations in the flap and active sites were required in each case for high-level resistance to occur, demonstrating that PL-100 has a high genetic barrier against the development of drug resistance.
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Asahchop
authors.forename: Maureen
authors.initials: M
authors.lastname: Oliveira
authors.forename: Bluma G
authors.initials: BG
authors.lastname: Brenner
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Martinez-Cajas
authors.forename: Thomas d'Aquin
authors.initials: Td
authors.lastname: Toni
authors.forename: Michel
authors.initials: M
authors.lastname: Ntemgwa
authors.forename: Daniela
authors.initials: D
authors.lastname: Moisi
authors.forename: Serge
authors.initials: S
authors.lastname: Dandache
authors.forename: Brent
authors.initials: B
authors.lastname: Stranix
authors.forename: Cecile L
authors.initials: CL
authors.lastname: Tremblay
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D002219:Carbamates; D017320:HIV Protease Inhibitors; C525732:PL 100; D013449:Sulfonamides; D016333:HIV Protease