17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

Co-evolved protease substrate cleavage site mutations enhance protease inhibitor phenotypic resistance

Antivir Ther. 2008; 13(Suppl. 3):A49 (abstract no. 44)

M Kolli¹, EW Stawiski², C Chappey², NT Parkin² and CA Schiffer^1
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA; ²Monogram Biosciences Inc., South San Francisco, CA 94080, USA

BACKGROUND: HIV-1 protease (PR) can acquire a multitude of mutations that confer resistance to protease inhibitors (PIs). These mutations may result in a less efficient PR and impaired viral fitness, leading to selection of compensatory mutations in PR and also in the substrate cleavage sites (CS). However, not much is known about the patterns and impact of Gag mutations on drug susceptibilities in combination with PR mutations.

METHODS: We analysed PI susceptibility of HIV-1 from more than 14,000 clinical samples as determined with the PhenoSense assay (Monogram Biosciences). Results are expressed as fold change (FC) in IC₅₀ (the half maximal inhibitory concentration) of the patient virus relative to that of the drug-sensitive reference, NL4-3. Primary drug resistance mutations at positions 30, 50, 82, 84 and 90 were the main focus of this study, using two levels of stringency for inclusion of secondary mutations. The statistical significance of the difference of median FC between groups with and without the Gag CS mutations was tested using the Mann–Whitney test.

RESULTS: Reduced susceptibility to nelfinavir and saquinavir was observed in viruses with D30N or D30N/N88D in combination with mutations at Gag L449. In addition, with D30N/N88D there were also small changes in susceptibilities in viruses that had mutations at S451, R452 and P453. Reduced susceptibility to lopinavir and indinavir was seen in viruses with V82A in combination with mutations at Gag A431 and L449. Reduced susceptibility to all PIs was observed in viruses with L90M in combination with mutations at Gag A431 (1.2- to 5.3-fold) and K436 (1.3- to 2.3-fold). Finally, changes in susceptibility to saquinavir and ritonavir were observed in viruses with V82A/L90M in combination with a mutation at Gag S451.

CONCLUSIONS: Enhanced PI resistance in HIV-1 is associated with the presence of Gag CS mutations. These studies suggest that substrate co-evolution might contribute to PI susceptibility in highly specific ways based on the particular combinations of mutations and inhibitors.

2008-06-10
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