Djeneba B Fofana1, Charlotte Charpentier2, Almoustapha I Maïga3, Sidonie Lambert-Niclot1, Sophie Sayon1, Nathalie Désiré1, Anne Simon4, Yazdan Yazdanpanah5, Christine Katlama6, Diane Descamps2, Vincent Calvez1, Anne-Geneviève Marcelin1, Cathia Soulié7. 1. Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013 Paris, France INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013 Paris, France AP-HP, Hôpital Pitié-Salpêtrière, Service de Virologie, F-75013 Paris, France. 2. IAME, UMR 1137, Université Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France IAME, UMR 1137, INSERM, F-75018 Paris, France AP-HP, Hôpital Bichat-Claude Bernard, laboratoire de Virologie, F-75018 Paris, France. 3. Unité d'Epidémiologie Moléculaire de la Résistance du VIH, SEREFO-FMOS/FAPH, Université des Sciences Techniques et des Technologies, Bamako, Mali Service de Laboratoire, CHU Gabriel Toure, Université des Sciences Techniques et des Technologies, Bamako, Mali. 4. AP-HP, Hôpital Pitié-Salpêtrière, Service de médecine interne, F-75013 Paris, France. 5. IAME, UMR 1137, Université Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France IAME, UMR 1137, INSERM, F-75018 Paris, France AP-HP, Hôpital Bichat-Claude Bernard, Service de maladies infectieuses, F-75018 Paris, France. 6. Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013 Paris, France INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013 Paris, France AP-HP, Hôpital Pitié-Salpêtrière, Service de maladies infectieuses, F-75013 Paris, France. 7. Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013 Paris, France INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013 Paris, France AP-HP, Hôpital Pitié-Salpêtrière, Service de Virologie, F-75013 Paris, France cathia.soulie@psl.aphp.fr.
Abstract
OBJECTIVES: The genetic barrier (defined as the number of genetic transitions/transversions needed to produce a resistance mutation) can differ between HIV-1 subtypes. The genetic barrier for the new attachment inhibitor BMS-626529 was evaluated in five HIV-1 subtypes. METHODS: Nine substitutions associated with BMS-626529 resistance at seven amino acid positions (116, 204, 375, 426, 434, 475 and 506) were analysed in 300 nucleotide sequences of the env gene encoding the gp120 protein from antiretroviral-naive patients (60 for each subtype and recombinant: B, C, D, CRF01_AE and CRF02_AG). RESULTS: Differently from the B subtype, some resistance mutations were found as natural polymorphisms in the C and D subtypes and the CRF02_AG and CRF01_AE recombinants for four positions of the env gene encoding the gp120 protein (375, 426, 434 and 475). The majority (five out of seven) of amino acid positions studied (116, 426, 434, 475 and 506) were relatively conserved (>63%) between the five HIV-1 subtypes, leading to a similar genetic barrier to mutations associated with resistance to BMS-626529. However, at positions 116 and 506 a minority of C and CRF02_AG subtypes had codons leading to a higher genetic barrier. Different predominant codons were observed at two out of seven positions (204 and 375) between the subtypes, with no effect on the calculated genetic barrier. However, for position 375, a minority of CRF02_AG sequences showed a lower genetic barrier to S375M/T resistance mutations. CONCLUSIONS: In non-B HIV-1 subtypes, four out of seven studied positions presented mutations implicated in BMS-626529 resistance. Despite great variability of the HIV-1 envelope, there was no major impact of polymorphisms on the genetic barrier to acquisition of BMS-626529 resistance.
OBJECTIVES: The genetic barrier (defined as the number of genetic transitions/transversions needed to produce a resistance mutation) can differ between HIV-1 subtypes. The genetic barrier for the new attachment inhibitor BMS-626529 was evaluated in five HIV-1 subtypes. METHODS: Nine substitutions associated with BMS-626529 resistance at seven amino acid positions (116, 204, 375, 426, 434, 475 and 506) were analysed in 300 nucleotide sequences of the env gene encoding the gp120 protein from antiretroviral-naive patients (60 for each subtype and recombinant: B, C, D, CRF01_AE and CRF02_AG). RESULTS: Differently from the B subtype, some resistance mutations were found as natural polymorphisms in the C and D subtypes and the CRF02_AG and CRF01_AE recombinants for four positions of the env gene encoding the gp120 protein (375, 426, 434 and 475). The majority (five out of seven) of amino acid positions studied (116, 426, 434, 475 and 506) were relatively conserved (>63%) between the five HIV-1 subtypes, leading to a similar genetic barrier to mutations associated with resistance to BMS-626529. However, at positions 116 and 506 a minority of C and CRF02_AG subtypes had codons leading to a higher genetic barrier. Different predominant codons were observed at two out of seven positions (204 and 375) between the subtypes, with no effect on the calculated genetic barrier. However, for position 375, a minority of CRF02_AG sequences showed a lower genetic barrier to S375M/T resistance mutations. CONCLUSIONS: In non-B HIV-1 subtypes, four out of seven studied positions presented mutations implicated in BMS-626529 resistance. Despite great variability of the HIV-1 envelope, there was no major impact of polymorphisms on the genetic barrier to acquisition of BMS-626529 resistance.
Authors: Margaret Gartland; Eric Arnoult; Brian T Foley; Max Lataillade; Peter Ackerman; Cyril Llamoso; Mark Krystal Journal: J Antimicrob Chemother Date: 2021-10-11 Impact factor: 5.790