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Journal of Virology, October 2009, p. 10245-10249, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00894-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Selective-Advantage Profile of Human Immunodeficiency Virus Type 1 Integrase Mutants Explains In Vivo Evolution of Raltegravir Resistance Genotypes{triangledown}

Romina Quercia,1,2 Elisabeth Dam,3 Danielle Perez-Bercoff,1 and François Clavel1,2*

INSERM U941, Paris F-75010, France,1 IUH, Université Paris-Diderot, Paris F-75010, France,2 BioAlliance Pharma, Paris F-75015, France3

Received 4 May 2009/ Accepted 15 July 2009

The emergence of human immunodeficiency virus type 1 resistance to raltegravir, an integrase strand transfer inhibitor, follows distinct and independent genetic pathways, among which the N155H and Q148HKR pathways are the most frequently encountered in treated patients. After prolonged viral escape, mutants of the N155H pathway are replaced by mutants of the Q148HKR pathway. We have examined the mechanisms driving this evolutionary pattern using an approach that assesses the selective advantage of site-directed mutant viruses as a function of drug concentration. These selective-advantage curves revealed that among single mutants, N155H had the highest and the widest (1 to 500 nM) selective-advantage profile. Despite the higher 50% inhibitory concentration, Q148H displayed a lower and narrower (10 to 100 nM) selective-advantage profile. Among double mutants, the highest and widest selective-advantage profile was seen with G140S+Q148H. This finding likely explains why N155H can be selected early in the course of RAL resistance evolution in vivo but is later replaced by genotypes that include Q148HKR.

* Corresponding author. Mailing address: INSERM U941, Bâtiment Hayem, Hôpital Saint Louis, 75475 Paris Cedex 10, France. Phone: (33) 1-4025-6363. Fax: (33) 1-4025-6370. E-mail: francois.clavel{at}inserm.fr

{triangledown} Published ahead of print on 15 July 2009.

Journal of Virology, October 2009, p. 10245-10249, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00894-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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