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HIV-1 subtype B and C integrase enzymes exhibit differential patterns of resistance to integrase inhibitors in biochemical assays

Bar-Magen, Tamaraa; Donahue, Daniel Aa,c; McDonough, Emily Ia; Kuhl, Björn Da,b; Faltenbacher, Verena Ha,*; Xu, Hongtaoa; Michaud, Veroniquea; Sloan, Richard Da; Wainberg, Mark Aa,b,c

doi: 10.1097/QAD.0b013e32833cf265
Basic Science

Background: Because of high intersubtype HIV-1 genetic variability, it has been shown that subtype-specific patterns of resistance to antiretroviral drugs exist. We wished to ascertain whether this might be true for integrase inhibitors.

Methods: We compared the susceptibility of subtype B and C HIV-1 integrase enzymes, harboring the previously reported resistance mutations E92Q, N155H, and E92Q/N155H, to clinically relevant integrase inhibitors. This was performed biochemically using a microtiter plate system.

Results: Subtype C integrase enzymes bearing the resistance mutations E92Q/N155H were approximately 10-fold more susceptible to each of two integrase inhibitors, raltegravir and elvitegravir, than were subtype B recombinant integrase containing the same mutations.

Conclusion: Polymorphic differences within the subtype B and C integrase genes likely cause variations in the contribution of N155H alone or in combination with E92Q to drug resistance. It is possible that different viral subtypes may favor different mutational pathways, potentially leading to varying levels of drug resistance among different subtypes.

aMcGill University AIDS Centre, Lady Davis Institute-Jewish General Hospital, Canada

bDivision of Experimental Medicine, Canada

cDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.

*Current Address: Ludwig-Maximilians-Universität, Munich, Germany.

Received 16 February, 2010

Revised 1 June, 2010

Accepted 8 June, 2010

Correspondence to Mark A. Wainberg, PhD, McGill University AIDS Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Côte-Ste-Catherine Road, Montréal, QC H3T 1E2, Canada. Tel: +1 514 340 8307; fax: +1 514 340 7537; e-mail: mark.wainberg@mcgill.ca

© 2010 Lippincott Williams & Wilkins, Inc.