title: The Second-Generation Maturation Inhibitor GSK3532795 Maintains Potent Activity Toward HIV Protease Inhibitor-Resistant Clinical Isolates.
abstract: Protease inhibitor (PI)-resistant HIV-1 isolates with primary substitutions in protease (PR) and secondary substitutions in Gag could potentially exhibit cross-resistance to maturation inhibitors. We evaluated the second-generation maturation inhibitor, GSK3532795, for activity toward clinical isolates with genotypic and phenotypic characteristics associated with PI resistance (longitudinal).
  
  
  
  Longitudinal clinical isolates from 15 PI-treated patients and 7 highly PI-resistant (nonlongitudinal) viruses containing major and minor PI resistance-associated mutations were evaluated for GSK3532795 sensitivity. Phenotypic sensitivity was determined using the PhenoSense Gag/PR assay (Monogram Biosciences) or in-house single- and multiple-cycle assays. Changes from baseline [CFB; ratio of post- to pre-treatment FC-IC50 (fold-change in IC50 versus wild-type virus)] <3 were considered to be within the no-effect level.
  
  
  
  All nonlongitudinal viruses tested were sensitive to GSK3532795 (FC-IC50 range 0.16-0.68). Among longitudinal isolates, all post-PI treatment samples had major PI resistance-associated mutations in PR and 17/21 had PI resistance-associated changes in Gag. Nineteen of the 21 post-PI treatment samples had GSK3532795 CFB <3. Median (range) CFB was 0.83 (0.05-27.4) [Monogram (11 patients)] and 1.5 (1.0-2.2) [single-cycle (4 patients)]. The 2 post-PI treatment samples showing GSK3532795 CFB >3 (Monogram) were retested using single- and multiple-cycle assays. Neither sample had meaningful sensitivity changes in the multiple-cycle assay. Gag changes were not associated with an increased GSK3532795 CFB.
  
  
  
  GSK3532795 maintained antiviral activity against PI-resistant isolates with emergent PR and/or Gag mutations. This finding supports continued development of GSK3532795 in treatment-experienced patients with or without previous PI therapy.
authors.affiliation: *Bristol-Myers Squibb, Research & Development, Princeton, NJ; †Bristol-Myers Squibb Virology, Wallingford, CT; ‡Currently, Tianbo Li, Genentech, South San Francisco, CA; Mark Krystal, Max Lataillade, and Ira Dicker, ViiV Healthcare, Wallingford, CT; §Department of Medical Microbiology, Virology, UMC Utrecht, Utrecht, the Netherlands; and ‖Currently, Carey Hwang, Global Clinical Development, Infectious Diseases, Merck, Kenilworth, NJ.
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Ray
authors.forename: Tianbo
authors.initials: T
authors.lastname: Li
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Lin
authors.forename: Tricia
authors.initials: T
authors.lastname: Protack
authors.forename: Petronella Maria
authors.initials: PM
authors.lastname: van Ham
authors.forename: Carey
authors.initials: C
authors.lastname: Hwang
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.forename: Monique
authors.initials: M
authors.lastname: Nijhuis
authors.forename: Max
authors.initials: M
authors.lastname: Lataillade
authors.forename: Ira
authors.initials: I
authors.lastname: Dicker
mesh_terms: D024882:Drug Resistance, Viral; D005838:Genotype; D060005:Genotyping Techniques; D006678:HIV / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification*; D015658:HIV Infections / Q000821:virology*; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008137:Longitudinal Studies; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease