Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants

被引：96

作者：

Kobayashi, Masanori ^{[1
]}

Nakahara, Koichiro ^{[1
]}

Seki, Takahiro ^{[1
]}

Miki, Shigeru ^{[1
]}

Kawauchi, Shinobu ^{[1
]}

Suyama, Akerni ^{[1
]}

Wakasa-Morimoto, Chiaki ^{[1
]}

Kodama, Makoto ^{[1
]}

Endoh, Takeshi ^{[1
]}

Oosugi, Eiichi ^{[1
]}

Matsushita, Yoshihiro ^{[1
]}

Murai, Hitoshi ^{[1
]}

Fujishita, Toshio ^{[1
]}

Yoshinaga, Tornokazu ^{[1
]}

Garvey, Edward ^{[2
]}

Foster, Scott ^{[2
]}

Underwood, Mark ^{[2
]}

Johns, Brian ^{[2
]}

Sato, Akihiko ^{[1
]}

Fujiwara, Tamio ^{[1
]}

机构：

[1] Shionogi & Co Ltd, Shionogi Res Labs, Settsu, Osaka 5660022, Japan

[2] GlaxoSmithKline, Infect Dis Ctr Excellence Drug Discovery, Res Triangle Pk, NC 27709 USA

来源：

ANTIVIRAL RESEARCH | 2008年 / 80卷 / 02期

关键词：

S/GSK-364735; S-1360; Integrase inhibitor; HIV; Resistance;

D O I：

10.1016/j.antiviral.2008.06.012

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 EC50 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 S-1360 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. (C) 2008 Elsevier B.V. All rights reserved.

引用

页码：213 / 222

页数：10

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