Selective-advantage profile of human immunodeficiency virus type 1 integrase mutants explains in vivo evolution of raltegravir resistance genotypes

Romina Quercia, Elisabeth Dam, Danielle Perez-Bercoff, François Clavel*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

44 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)10245-10249
Number of pages5
JournalJournal of Virology
Volume83
Issue number19
DOIs
Publication statusPublished - Oct 2009
Externally publishedYes

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