|
16th International HIV Drug Resistance Workshop12-16 June 2007, Barbados |
HIV-1 INTEGRASE SEQUENCE VARIATION AND COVARIATION
Antivir Ther. 2007; 12:S5 (abstract no. 3)
RE Myers1 and D Pillay1,2
1Virus Reference Department, Health Protection Agency, London, UK; 2Centre for Virology, Department of Infection, University College London, UK
BACKGROUND: Integrase inhibitors (Raltegravir and GS- 9137) are the latest class of antiretroviral therapeutics used to treat HIV-1. Identifying and predicting resistance to this class of inhibitors is critical to their efficacy within a clinical context. Clinical trials and in vitro resistance studies to integrase inhibitors have resulted in an extensive list of amino acid mutations that affect sensitivity to these drugs.
METHODS: One-thousand, two-hundred and fifty integrase inhibitor-naïve sequences encompassing all HIV-1 subtypes and groups (Los Alamos) were analysed for subtype diversity, the prevalence of resistance mutations and covariation. Amino acid covariation was determined using the Jaccard index, modified to include a novel weighting component that minimized the effect of phylogenetic relatedness within a sequence population.
RESULTS: Fourty-one resistance-associated mutations were considered in 30 positions within HIV-1 integrase and 25 of these mutations were identified in inhibitornaïve sequences (n=1,250, all subtypes). The most prevalent variants were V201I (80%) and V72I (46%). Other mutations were less common; however, there was significant subtype association of mutations, 15 out of 25 positive positions exhibited >5% frequency of a resistance mutation within one or more subtypes. Subtypes A (n=193), B (n=268) and C (n=404) were also tested for the presence of amino acid covariation within drug-naïve integrase sequences. Thirty-three percent of amino acid positions that showed statistical covariation were unique to a subtype, the remainder (67%) were observed independent of subtype. A network of covariance was demonstrated between eight established resistance mutations (amino acids 72, 74, 97, 125, 154, 163, 201 and 206), highlighting putative functional relationships between these positions. Eleven of the 30 positions implicated in integrase resistance were shown to covary with other amino acids, suggesting a possible role for mutations at these novel positions affecting drug susceptibly.
CONCLUSIONS: This analysis of sequence variation within HIV-1 integrase highlights strains and subtypes of HIV-1 that may be less susceptible to integrase inhibitors and interactions between amino acid positions, determined by covariation, which should be examined by in vitro and structural methods. Our data suggest that baseline susceptibility in vivo and the barriers to emergence of resistance may differ between the group M subtypes.
2007-06-12
3
Copyright © 2006 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.