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J. Virol. doi:10.1128/JVI.01534-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Broad Anti-Retroviral Activity and Resistance Profile of a Novel Human Immunodeficiency Virus Integrase Inhibitor, Elvitegravir (JTK-303/GS-9137)

Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Japan Tobacco Inc., Central Pharmaceutical Research Institute, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan; Japan Tobacco Inc., Central Pharmaceutical Research Institute, Pharmaceutical Frontier Research Laboratories, 1-13-2 Fukuura, Kanazawa-Ku, Yokohama, Kanagawa 236-0004, Japan

^* To whom correspondence should be addressed. Email: ekodama{at}virus.kyoto-u.ac.jp.

	Abstract

Integrase (IN), an essential enzyme of human immunodeficiency virus (HIV), is an attractive antiretroviral drug target. The antiviral activity and resistance profile in vitro of a novel IN inhibitor, elvitegravir (EVG, also known as JTK-303/GS-9137), currently being developed for the treatment of HIV-1 infection, are described. EVG blocked the integration of the HIV-1 cDNA through inhibition of DNA strand transfer. EVG inhibited replication of HIV-1 including various subtypes and multiple drug-resistant clinical isolates, and HIV-2 strains with a 50% effective concentration in the sub-nanomolar to nanomolar range. EVG-resistant variants were selected in two independent inductions and a total of eight amino acid substitutions in the catalytic core domain of IN were observed. Among the observed IN mutations, T66I and E92Q substitutions mainly contributed to EVG resistance. These two primary resistance mutations are located in the active site and other secondary mutations identified are proximal to these primary mutations. The EVG-selected IN mutations, some of which represent novel IN inhibitor resistance mutations, conferred reduced susceptibility to other IN inhibitors suggesting that a common mechanism is involved in resistance and potential cross-resistance. The replication capacity of EVG-resistant variants was significantly reduced relative to both wild-type virus and other IN inhibitor-resistant variants selected by L-870,810. EVG and L-870,810 both inhibited replication of murine leukemia virus and simian immunodeficiency virus, suggesting that IN inhibitors bind to a conformationally conserved region of various retroviral IN enzymes and are an ideal drug for a range of retroviral infections.

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