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Antimicrob. Agents Chemother. doi:10.1128/AAC.01228-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mutations Associated with Failure of Raltegravir Treatment affect integrase sensitivity to the inhibitor in vitro

Laboratoire de Virologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; EA 2387, Université Pierre et Marie Curie (Paris 6), Paris, France; LBPA, CNRS, Ecole Normale Supérieure de Cachan, France; INSERM U720, Université Pierre et Marie Curie (Paris 6), France; Service des Maladies Infectieuses, Hôpital Pitié-Salpêtrière Paris; Pôle Infectiologie, CHU de Montpellier, 34 295 Montpellier; Service de Pharmacie Clinique, Hôpital Bichat-Claude-Bernard, 46, rue Henri-Huchard, 75018 Paris, France

^* To whom correspondence should be addressed. Email: isabelle.malet{at}psl.aphp.fr.

	Abstract

Raltegravir (MK-0518) is a potent inhibitor of HIV integrase and is clinically effective against viruses resistant to other classes of antiretroviral agents. However, it can select mutations in the HIV integrase gene. Nine heavily pretreated patients who received a salvage therapy including raltegravir and who subsequently developed virological failure under raltegravir therapy were studied. For each patient, sequences of integrase-coding region were determined and compared to that at the beginning of the treatment. Four different mutation profiles were identified in these nine patients: E92Q, G140S + Q148H, N155H and E157Q mutations. For four patients, each harboring a different profile, the wild-type and mutated integrases were produced, purified and assayed in vitro. All the identified mutations altered the activities of integrase protein: E92Q was moderately affected for both 3' processing and strand transfer activities; N155H was markedly impaired for strand transfer; G140S + Q148H was strongly impaired for both activities; and E157Q was almost completely inactive for both activities. The sensitivities of wild-type and mutant integrases to raltegravir were compared. The profiles E92Q and G140S + Q148H were each associated with a 7- to 8-fold decrease in sensitivity, and N155H was more than 14-fold less sensitive to raltegravir. At least four genetic profiles (E92Q, G140S + Q148H, N155H and E157Q) can be associated with in vivo treatment failure and resistance to raltegravir. These mutations led to enzymes strongly impaired in vitro in the absence of raltegravir, strand transfer activity was affected and in some cases the 3' processing was also impaired.

This article has been cited by other articles:

• Havlir, D. V. (2008). HIV Integrase Inhibitors -- Out of the Pipeline and into the Clinic. NEJM 359: 416-418 [Full Text]