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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Polymorphisms of HIV-2 integrase and selection of resistance to raltegravir
Retrovirology, Volume 7, Article 98, Year 2010
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Description
Background: Human Immunodeficiency Virus type 2 is naturally resistant to some antiretroviral drugs, restricting therapeutic options for patients infected with HIV-2. Regimens including integrase inhibitors (INI) seem to be effective, but little data on HIV-2 integrase (IN) polymorphisms and resistance pathways are available.Materials and methods: The integrase coding sequence from 45 HIV-2-infected, INI-naïve, patients was sequenced and aligned against the ROD (group A) or EHO (group B) reference strains and polymorphic or conserved positions were analyzed.To select for raltegravir (RAL)-resistant variants in vitro, the ROD strain was cultured under increasing sub-optimal RAL concentrations for successive rounds. The phenotype of the selected variants was assessed using an MTT assay.Results: We describe integrase gene polymorphisms in HIV-2 clinical isolates from 45 patients. Sixty-seven percent of the integrase residues were conserved. The HHCC Zinc coordination motif, the catalytic triad DDE motif, and AA involved in IN-DNA binding and correct positioning were highly conserved and unchanged with respect to HIV-1 whereas the connecting residues of the N-terminal domain, the dimer interface and C-terminal LEDGF binding domain were highly conserved but differed from HIV-1. The N155 H INI resistance-associated mutation (RAM) was detected in the virus population from one ARV-treated, INI-naïve patient, and the 72I and 201I polymorphisms were detected in samples from 36 and 38 patients respectively. No other known INI RAM was detected.Under RAL selective pressure in vitro, a ROD variant carrying the Q91R+I175M mutations was selected. The Q91R and I175M mutations emerged simultaneously and conferred phenotypic resistance (13-fold increase in IC50). The Q91R+I175M combination was absent from all clinical isolates. Three-dimensional modeling indicated that residue 91 lies on the enzyme surface, at the entry of a pocket containing the DDE catalytic triad and that adding a positive charge (Gln to Arg) might compromise IN-RAL affinity.Conclusions: HIV-2 polymorphisms from 45 INI-naïve patients are described. Conserved regions as well as frequencies of HIV-2 IN polymorphisms were comparable to HIV-1. Two new mutations (Q91R and I175M) that conferred high resistance to RAL were selected in vitro, which might affect therapeutic outcome. © 2010 Bercoff et al; licensee BioMed Central Ltd.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3006360/bin/1742-4690-7-98-S1.DOC
https://efashare.b-cdn.net/share/pmc/articles/PMC3006360/bin/1742-4690-7-98-S2.PDF
Authors & Co-Authors
Perez-Bercoff, Danielle
Luxembourg, Luxembourg
Retrovirology Laboratory Luxembourg
Triqueneaux, Perrine
Belgium, Louvain-la-neuve
Université Catholique de Louvain
Lambert, Christine
Luxembourg, Luxembourg
Retrovirology Laboratory Luxembourg
Oumar, Aboubacar Alassane
Mali, Bamako
University of Bamako Faculty of Medicine, Pharmacy and Odonto-stomatology
Ternes, Anne Marie
Luxembourg, Luxembourg
Retrovirology Laboratory Luxembourg
Dao, Sounkalo Z.
Mali, Bamako
University of Bamako Faculty of Medicine, Pharmacy and Odonto-stomatology
Goubau, Patrick
Belgium, Louvain-la-neuve
Université Catholique de Louvain
Schmit, Jean Claude
Luxembourg, Luxembourg
Retrovirology Laboratory Luxembourg
Ruelle, Jean
Belgium, Louvain-la-neuve
Université Catholique de Louvain
Statistics
Citations: 24
Authors: 9
Affiliations: 3
Identifiers
Doi:
10.1186/1742-4690-7-98
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Infectious Diseases
Study Design
Cross Sectional Study