Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants.
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.
Kobayashi
Masanori
M
Virology, Shionogi Research Laboratories, Shionogi & Co Ltd, Osaka, Japan.
Nakahara
Koichiro
K
Seki
Takahiro
T
Miki
Shigeru
S
Kawauchi
Shinobu
S
Suyama
Akemi
A
Wakasa-Morimoto
Chiaki
C
Kodama
Makoto
M
Endoh
Takeshi
T
Oosugi
Eiichi
E
Matsushita
Yoshihiro
Y
Murai
Hitoshi
H
Fujishita
Toshio
T
Yoshinaga
Tomokazu
T
Garvey
Edward
E
Foster
Scott
S
Underwood
Mark
M
Johns
Brian
B
Sato
Akihiko
A
Fujiwara
Tamio
T
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
D019428:HIV Integrase Inhibitors; D019427:HIV Integrase