title: Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants.
abstract: Resistance passage studies were conducted with five INIs (integrase inhibitors) that have been tested in clinical trials to date: a new naphthyridinone-type INI S/GSK-364735, raltegravir, elvitegravir, L-870,810 and S-1360. In establishing the passage system and starting from concentrations several fold above the EC(50) value, resistance mutations against S-1360 and related diketoacid-type compounds could be isolated from infected MT-2 cell cultures from day 14 to 28. Q148R and F121Y were the two main pathways of resistance to S/GSK-364735. Q148R/K and N155H, which were found in patients failing raltegravir treatment in Phase IIb studies, were observed during passage with raltegravir with this method. The fold resistance of 40 mutant molecular clones versus wild type virus was compared with these five INIs. The overall resistance pattern of S/GSK-364735 was similar to that of raltegravir and other INIs. However, different fold resistances of particular mutations were noted among different INIs, reflecting a potential to develop INIs with distinctly different resistant profiles.
authors.affiliation: Virology, Shionogi Research Laboratories, Shionogi & Co Ltd, Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Nakahara
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miki
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kawauchi
authors.forename: Akemi
authors.initials: A
authors.lastname: Suyama
authors.forename: Chiaki
authors.initials: C
authors.lastname: Wakasa-Morimoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Endoh
authors.forename: Eiichi
authors.initials: E
authors.lastname: Oosugi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsushita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Murai
authors.forename: Toshio
authors.initials: T
authors.lastname: Fujishita
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Yoshinaga
authors.forename: Edward
authors.initials: E
authors.lastname: Garvey
authors.forename: Scott
authors.initials: S
authors.lastname: Foster
authors.forename: Mark
authors.initials: M
authors.lastname: Underwood
authors.forename: Brian
authors.initials: B
authors.lastname: Johns
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sato
authors.forename: Tamio
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics* / Q000302:isolation & purification; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D013601:T-Lymphocytes / Q000821:virology
chemical_list: D019428:HIV Integrase Inhibitors; D019427:HIV Integrase