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Nucleic Acids Research Advance Access published online on January 7, 2009
Nucleic Acids Research, doi:10.1093/nar/gkn1050
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation

Olivier Delelis1,*, Isabelle Malet2, Li Na1, Luba Tchertanov1, Vincent Calvez2, Anne-Genevieve Marcelin2, Frederic Subra1, Eric Deprez1 and Jean-François Mouscadet1

1LBPA, CNRS, Ecole Normale Supérieure de Cachan, 94235 Cachan and 2Laboratoire de Virologie, Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie, 75013 Paris, France

*To whom correspondence should be addressed. Tel: +33 1 47 40 77 26; Fax: +33 1 47 40 76 84; Email: delelis{at}lbpa.ens-cachan.fr

Received November 19, 2008. Revised December 12, 2008. Accepted December 15, 2008.

Raltegravir (MK-0518) is the first integrase (IN) inhibitor to be approved by the US FDA and is currently used in clinical treatment of viruses resistant to other antiretroviral compounds. Virological failure of Raltegravir treatment is associated with mutations in the IN gene following two main distinct genetic pathways involving either the N155 or Q148 residue. Importantly, in most cases, an additional mutation at the position G140 is associated with the Q148 pathway. Here, we investigated the viral DNA kinetics for mutants identified in Raltegravir-resistant patients. We found that (i) integration is impaired for Q148H when compared with the wild-type, G140S and G140S/Q148H mutants; and (ii) the N155H and G140S mutations confer lower levels of resistance than the Q148H mutation. We also characterized the corresponding recombinant INs properties. Enzymatic performances closely parallel ex vivo studies. The Q148H mutation ‘freezes’ IN into a catalytically inactive state. By contrast, the conformational transition converting the inactive form into an active form is rescued by the G140S/Q148H double mutation. In conclusion, the Q148H mutation is responsible for resistance to Raltegravir whereas the G140S mutation increases viral fitness in the G140S/Q148H context. Altogether, these results account for the predominance of G140S/Q148H mutants in clinical trials using Raltegravir.


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