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JAC Advance Access published online on September 1, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn338
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Impact of gag mutations on selection of darunavir resistance mutations in HIV-1 protease

Sidonie Lambert-Niclot1,2,*, Philippe Flandre3, Isabelle Malet1,2, Ana Canestri3,4, Cathia Soulié1,2, Roland Tubiana3,4, Christel Brunet1,2, Marc Wirden1,2, Christine Katlama3,4, Vincent Calvez1,2 and Anne-Geneviève Marcelin1,2

1 UPMC Univ Paris 06, EA 2387, F-75005, Paris, France 2 AP-HP, Hôpital Pitié Salpêtrière, Laboratoire de Virologie, F-75013, Paris, France 3 INSERM U720, F-75013, Paris, France 4 AP-HP, Hôpital Pitié Salpêtrière, Service de Maladies Infectieuses, F-75013, Paris, France

Received 16 May 2008; returned 17 July 2008; revised 28 July 2008; accepted 29 July 2008

* Correspondence address. Department of Virology, Pitié-Salpêtrière Hospital, 83 Boulevard de l'Hôpital, 75013 Paris, France. Tel: +33-142177409; Fax: +33-142177411; E-mail: sidonie.lambert{at}psl.aphp.fr

Objectives: To search for genetic factors in the protease and gag regions (NC-p1/TFP-p6/p6pol) involved in selection of darunavir resistance mutations.

Patients and methods: We analysed 48 protease inhibitor (PI)-experienced HIV-infected patients experiencing darunavir treatment failure. Viral genotyping at baseline and months 3 and 6 was used to assess the selection of mutations in the protease and gag regions conferring resistance to PIs.

Results: There were no genotypic differences in the studied gag region between baseline and the latest available rebound isolates. There was an association between the presence of the mutation A431V in the gag sequence and the selection of the L76V mutation in the protease sequence in the latest available rebound. The I437T/V mutation in gag and the L76V mutation in the protease were associated with a lower risk of selecting darunavir resistance mutations.

Conclusions: In these PI-treated patients experiencing treatment failure of a darunavir-containing regimen, we showed that mutations in the gag region NC-p1/TFP-p6/p6pol may influence the selection of darunavir resistance mutations; in particular, the I437T/V gag mutation that confers resistance to PIs reduces the selection of such mutations. Virus with L76V in protease or I437T/V in gag may be already resistant to darunavir and, therefore, no additional resistance mutations need to be selected.

Key Words: HIV , drug resistance , protease inhibitors , risk factors


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