Than for HIV-1. Raltegravir, an integrase inhibitor, is active against wild-typeThan for HIV-1. Raltegravir, an

Than for HIV-1. Raltegravir, an integrase inhibitor, is active against wild-type
Than for HIV-1. Raltegravir, an integrase inhibitor, is active against wild-type HIV-2, with a susceptibility to this PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28242652 drug similar to that of HIV-1, and is therefore a promising option for use in the treatment of HIV-2-infected patients. Recent studies have shown that HIV-2 resistance to raltegravir involves one of three resistance mutations, N155H, Q148R/H and Y143C, previously identified as resistance determinants in the HIV1 integrase coding sequence. The resistance of HIV-1 IN has been confirmed in vitro for mutated enzymes harboring these mutations, but no such confirmation has yet been obtained for HIV-2. Results: The integrase coding sequence was amplified from plasma samples collected from ten patients infected with HIV-2 viruses, of whom three RAL-na e and seven on RAL-based treatment at the time of virological failure. The genomes of the resistant strains were cloned and three patterns involving N155H, G140S/Q148R or Y143C mutations were identified. Study of the susceptibility of integrases, either amplified from clinical isolates or obtained by mutagenesis demonstrated that mutations at positions 155 and 148 render the integrase resistant to RAL. The G140S mutation conferred little resistance, but compensated for the catalytic defect due to the Q148R mutation. Conversely, Y143C alone did not confer resistance to RAL unless E92Q is also present. Furthermore, the introduction of the Y143C mutation into the N155H resistant background decreased the resistance level of enzymes containing the N155H mutation. Conclusion: This study confirms that HIV-2 resistance to RAL is due to the N155H, G140S/Q148R or E92Q/Y143C mutations. The N155H and G140S/Q148R mutations make similar contributions to resistance in both HIV-1 and HIV2, but Y143C is not sufficient to account for the resistance of HIV-2 genomes harboring this mutation. For Y143C to confer resistance in vitro, it must be accompanied by E92Q, which therefore plays a more important role in the HIV-2 context than in the HIV-1 context. Finally, the Y143C mutation counteracts the resistance conferred by the N155H mutation, probably accounting for the lack of detection of these mutations together in a single genome. Keywords: HIV-2, integrase, raltegravir, resistance, mutationBackground HIV-2 is endemic in West Africa and has spread throughout Europe over the last two decades [1,2]. The development of seven different classes of antiretroviral drugs has led to the establishment of highly active treatments that have had a profound effect on the morbidity* Correspondence: [email protected] 1 LBPA, CNRS, Ecole Normale Sup ieure de Cachan, Cachan, France Full list of author information is available at the end of the articleand mortality of HIV-1-infected individuals. These classes are nucleoside (NRTIs), nucleotide (NtRTIs) PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28549975 and non nucleoside (NNRTIs) reverse transcriptase inhibitors, protease inhibitors (PIs), entry inhibitors, fusion inhibitors and integrase (IN) inhibitors (INIs). Despite this apparent diversity, the alternatives for HIV-2infected patients are more limited because NNRTIs and fusion inhibitors are not active against HIV-2 [3,4] and HIV-2 is also less sensitive to some PIs [5-7]. It has also?2011 Ni et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which 5-BrdU biological activity permits unrestricted use, distribution, and reproduction in any medium, prov.