The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype

Isabelle Malet, Slim Fourati, Charlotte Charpentier, Laurence Morand-Joubert, Daniele Armenia, Marc Wirden, Sophie Sayon, Margriet Van houtte, Francesca Ceccherini-Silberstein, Françoise Brun-Vézinet, Carlo Federico Perno, Diane Descamps, André Capt, Vincent Calvez, Anne Geneviève Marcelin

Research output: Contribution to journalArticle

Abstract

Background: Most of the previous studies that explored the molecular basis of raltegravir resistance were conducted studying the HIV-1 B subtype. It has been shown that the CRF02_AG subtype in relation to its natural integrase (IN) sequence could develop different genetic pathways associated with raltegravir resistance. The aim of this study was to explore resistance pathways preferably used by CRF02_AG viruses compared with subtype B. Methods: Twenty-five HIV-1 CRF02_AG-infected patients failing a raltegravir-containing regimen were studied. IN gene sequences were examined for the presence of previously described IN inhibitor (raltegravir, elvitegravir, dolutegravir and MK-2048) resistance mutations at 20 amino acid positions. Results: Among the 25 studied patients, 7 showed viruses harbouring major raltegravir resistance mutations mainly associated with the 155 genetic pathways and 18 showed viruses harbouring none of them; however, for 1 patient, we found a 118R mutation, associated with MK-2048 in vitro resistance, in a 74M background. For this patient, the phenotypic analysis showed that addition of only the G118R mutation conferred a high level of resistance to raltegravir (fold change=25.5) and elvitegravir (fold change=9.2). Conclusions: This study confirmed that mutation pathways for raltegravir resistance could be different between the two subtypes CRF02_AG and B with a preferential use of the 155 mutation in non-B subtypes. A new genetic pathway associated with raltegravir resistance, including the 118R mutation, has also been identified. This new genetic pathway, never described in subtype B, should be further evaluated for phenotypic susceptibility to dolutegravir and MK-2048.

Original languageEnglish
Article numberdkr389
Pages (from-to)2827-2830
Number of pages4
JournalJournal of Antimicrobial Chemotherapy
Volume66
Issue number12
DOIs
Publication statusPublished - Dec 2011

Fingerprint

HIV-1
Mutation
Integrases
Viruses
Integrase Inhibitors
Raltegravir Potassium
p31 integrase protein, Human immunodeficiency virus 1
Amino Acids
Genes

Keywords

  • Integrase inhibitors
  • MK-2048
  • Phenotype

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Malet, I., Fourati, S., Charpentier, C., Morand-Joubert, L., Armenia, D., Wirden, M., ... Marcelin, A. G. (2011). The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype. Journal of Antimicrobial Chemotherapy, 66(12), 2827-2830. [dkr389]. https://doi.org/10.1093/jac/dkr389

The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype. / Malet, Isabelle; Fourati, Slim; Charpentier, Charlotte; Morand-Joubert, Laurence; Armenia, Daniele; Wirden, Marc; Sayon, Sophie; Van houtte, Margriet; Ceccherini-Silberstein, Francesca; Brun-Vézinet, Françoise; Perno, Carlo Federico; Descamps, Diane; Capt, André; Calvez, Vincent; Marcelin, Anne Geneviève.

In: Journal of Antimicrobial Chemotherapy, Vol. 66, No. 12, dkr389, 12.2011, p. 2827-2830.

Research output: Contribution to journalArticle

Malet, I, Fourati, S, Charpentier, C, Morand-Joubert, L, Armenia, D, Wirden, M, Sayon, S, Van houtte, M, Ceccherini-Silberstein, F, Brun-Vézinet, F, Perno, CF, Descamps, D, Capt, A, Calvez, V & Marcelin, AG 2011, 'The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype', Journal of Antimicrobial Chemotherapy, vol. 66, no. 12, dkr389, pp. 2827-2830. https://doi.org/10.1093/jac/dkr389
Malet I, Fourati S, Charpentier C, Morand-Joubert L, Armenia D, Wirden M et al. The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype. Journal of Antimicrobial Chemotherapy. 2011 Dec;66(12):2827-2830. dkr389. https://doi.org/10.1093/jac/dkr389
Malet, Isabelle ; Fourati, Slim ; Charpentier, Charlotte ; Morand-Joubert, Laurence ; Armenia, Daniele ; Wirden, Marc ; Sayon, Sophie ; Van houtte, Margriet ; Ceccherini-Silberstein, Francesca ; Brun-Vézinet, Françoise ; Perno, Carlo Federico ; Descamps, Diane ; Capt, André ; Calvez, Vincent ; Marcelin, Anne Geneviève. / The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype. In: Journal of Antimicrobial Chemotherapy. 2011 ; Vol. 66, No. 12. pp. 2827-2830.
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abstract = "Background: Most of the previous studies that explored the molecular basis of raltegravir resistance were conducted studying the HIV-1 B subtype. It has been shown that the CRF02_AG subtype in relation to its natural integrase (IN) sequence could develop different genetic pathways associated with raltegravir resistance. The aim of this study was to explore resistance pathways preferably used by CRF02_AG viruses compared with subtype B. Methods: Twenty-five HIV-1 CRF02_AG-infected patients failing a raltegravir-containing regimen were studied. IN gene sequences were examined for the presence of previously described IN inhibitor (raltegravir, elvitegravir, dolutegravir and MK-2048) resistance mutations at 20 amino acid positions. Results: Among the 25 studied patients, 7 showed viruses harbouring major raltegravir resistance mutations mainly associated with the 155 genetic pathways and 18 showed viruses harbouring none of them; however, for 1 patient, we found a 118R mutation, associated with MK-2048 in vitro resistance, in a 74M background. For this patient, the phenotypic analysis showed that addition of only the G118R mutation conferred a high level of resistance to raltegravir (fold change=25.5) and elvitegravir (fold change=9.2). Conclusions: This study confirmed that mutation pathways for raltegravir resistance could be different between the two subtypes CRF02_AG and B with a preferential use of the 155 mutation in non-B subtypes. A new genetic pathway associated with raltegravir resistance, including the 118R mutation, has also been identified. This new genetic pathway, never described in subtype B, should be further evaluated for phenotypic susceptibility to dolutegravir and MK-2048.",
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AU - Malet, Isabelle

AU - Fourati, Slim

AU - Charpentier, Charlotte

AU - Morand-Joubert, Laurence

AU - Armenia, Daniele

AU - Wirden, Marc

AU - Sayon, Sophie

AU - Van houtte, Margriet

AU - Ceccherini-Silberstein, Francesca

AU - Brun-Vézinet, Françoise

AU - Perno, Carlo Federico

AU - Descamps, Diane

AU - Capt, André

AU - Calvez, Vincent

AU - Marcelin, Anne Geneviève

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