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Phenotypic susceptibility and drug resistance profile of HIV-1 B, C and AG clones selected with atazanavir, lopinavir and nelfinavir
I. Lisovsky, J.L. Martinez Cajas, M. Oliveira, D. Moisi, O. Golubkov, M.A. Wainberg
Lady Davis Institute, Jewish General Hospital, McGill University AIDS Centre, Montreal, Canada
Background The genetic differences between HIV-1 subtypes prevalent in Africa (A, AG & C) and the Western World (B) have been documented. However, antiretroviral therapy (ART) has been designed against subtype B HIV-1. With the advent of ART in developing countries and the emergence of non-B subtype infections in developed countries, the impact of these genetic differences must be evaluated in terms of ART efficacy. We investigated the phenotypic susceptibility and the emergence of drug resistance mutations among HIV-1 B, C and AG viral clones selected with the protease inhibitors (PIs) Atazanavir (ATV), lopinavir (LPV) and nelfinavir (NFV) in vitro.
Methods293T cells were used to produce HIV-1 B, C and AG viruses from molecular clones via transfection. Cord blood mononuclear cells (CBMCs) were infected at half the maximal inhibitory concentration of each PI and selection for resistance was performed by growing the cultures under increasing concentrations of PIs. Each week, culture supernatants were tested for viral replication based on RT activity and PI concentrations were adjusted accordingly. Viruses able to replicate under PI pressure were genotyped and phenotyped to analyze emerging mutational patterns and ascertain the level of resistance to the PIs.
ResultsDifferences were observed in the acquisition of drug resistance mutations after 25 weeks. Furthermore, viral subtypes varied in their ability to replicate under incremental adjustments of PIs used. For example, LPV concentration was increased more rapidly in subtype AG virus compared to B & C viruses. IC50 fold increases for drug selected viruses were 3 to 62 fold greater than preselection data.
ConclusionHIV-1 subtype specific clones tested present with different resistance mutations and have different phenotypic susceptibility to the same PI. Genetic diversity among subtypes may have an impact on mutation acquisition and drug susceptibility. These findings may shed light how PI are administered to patients infected with specific HIV-1 subtypes.
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