title: In vitro analysis of the susceptibility of HIV-1 subtype A and CRF01_AE integrases to raltegravir.
abstract: The antiviral efficacy of raltegravir (RAL) has been proven against human immunodeficiency virus type 1 (HIV-1) subtypes B and C but remained to be determined against other subtypes. Therefore, the enzymatic activities as well as RAL resistance of HIV-1 subtype A and CRF01_AE integrases (INs) were investigated. Previously published subtype A and CRF01_AE IN sequences from RAL-naïve patients were aligned to generate consensus sequences for both IN subtypes. Subtype A and CRF01_AE INs encoded by these consensus sequences as well as the corresponding enzymes harbouring the N155H resistance mutation were expressed and purified. Enzymatic activities of subtype A and CRF01_AE INs were analysed with regard to typical 3'-end processing (3'-P) and strand transfer (ST) activities both in the presence and absence of RAL and were compared with subtype B IN as well as with the corresponding INs harbouring the N155H resistance mutation. Subtypes B, A and CRF01_AE INs showed similar 3'-P and ST activities. In the presence of RAL, the three wild-type INs exhibited ST activity IC50 values (50% inhibitory concentrations) of 86.3 ± 32.5, 158.3 ± 99.0 and 100.0 ± 65.7 nM, respectively. Analysis of 3'-P activity in the presence of RAL revealed IC(50) > 10 μM for all three enzymes. The three INs harbouring the N155H mutation presented in vitro low but similar resistance levels to RAL. In conclusion, INs from HIV-1 subtypes B, A and CRF01_AE showed similar responses to RAL in vitro, suggesting the potency of this antiretroviral drug to treat HIV-1 subtype A- and CRF01_AE-infected patients.
authors.affiliation: Laboratoire de Virologie, Hôpital Pellegrin, CHU, Bordeaux, France; MFP, UMR 5234-CNRS, Université Bordeaux Segalen, Bordeaux, France; Structure Fédérative de Recherche 'TransbioMed', Bordeaux, France.
authors.forename: Pantxika
authors.initials: P
authors.lastname: Bellecave
authors.affiliation: Laboratoire de Virologie, Hôpital Pellegrin, CHU, Bordeaux, France; MFP, UMR 5234-CNRS, Université Bordeaux Segalen, Bordeaux, France; Structure Fédérative de Recherche 'TransbioMed', Bordeaux, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Malato
authors.affiliation: MFP, UMR 5234-CNRS, Université Bordeaux Segalen, Bordeaux, France; Structure Fédérative de Recherche 'TransbioMed', Bordeaux, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Calmels
authors.affiliation: Laboratoire de Virologie, Hôpital Pellegrin, CHU, Bordeaux, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Reigadas
authors.affiliation: MFP, UMR 5234-CNRS, Université Bordeaux Segalen, Bordeaux, France; Structure Fédérative de Recherche 'TransbioMed', Bordeaux, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Parissi
authors.affiliation: MFP, UMR 5234-CNRS, Université Bordeaux Segalen, Bordeaux, France; Structure Fédérative de Recherche 'TransbioMed', Bordeaux, France. Electronic address: marie-line.andreola@reger.u-bordeaux2.fr.
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Andreola
authors.affiliation: Laboratoire de Virologie, Hôpital Pellegrin, CHU, Bordeaux, France; MFP, UMR 5234-CNRS, Université Bordeaux Segalen, Bordeaux, France; Structure Fédérative de Recherche 'TransbioMed', Bordeaux, France. Electronic address: herve.fleury@viro.u-bordeaux2.fr.
authors.forename: Hervé
authors.initials: H
authors.lastname: Fleury
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D003001:Cloning, Molecular; D015870:Gene Expression; D005838:Genotype; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium
chemical_list: D019380:Anti-HIV Agents; D050505:Mutant Proteins; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: CRF01_AE HIV-1; Inhibition; Integrase; Raltegravir; Subtype A HIV-1