New raltegravir resistance pathways induce broad cross-resistance to all currently used integrase inhibitors.
OBJECTIVE
The possibility of replacing raltegravir or elvitegravir with dolutegravir in heavily treatment-experienced patients failing on raltegravir/elvitegravir has been evaluated in VIKING trials. All studied patients failed by the most common pathways, Y143, Q148 and N155, and dolutegravir demonstrated efficacy except for Q148 viruses. The aim of this study was to explore, in the same way, the behaviour of dolutegravir in comparison with raltegravir and elvitegravir against the atypical resistance integrase profiles, G118R and F121Y, described in HIV-1 patients failing on raltegravir therapy.


METHODS
The behaviour of integrases with mutations G118R and F121Y towards raltegravir, elvitegravir and dolutegravir was analysed by evaluating phenotypic susceptibility and by means of in silico techniques (investigating binding affinities and the stabilization of the inhibitors in terms of their hydrogen bond network).


RESULTS
The phenotypic analysis of G118R and F121Y showed high resistance to raltegravir, elvitegravir and dolutegravir with a fold change >100 when the clinically derived integrase was used, and resistance was also seen when mutations were tested alone in an NL43 backbone, but more often with a lower fold change. In silico, results showed that G118R and F121Y enzymes were associated with reduced binding affinities to each of the inhibitors and with a decreased number of hydrogen bonds compared with the wild-type complexes.


CONCLUSIONS
This study showed that G118R and F121Y mutations, rarely described in patients failing on raltegravir, induced broad cross-resistance to all currently used integrase inhibitors. These results are in accordance with our thermodynamic and geometric analysis indicating decreased stability compared with the wild-type complexes.
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, Laboratoire de Virologie, Hôpital Pité-Salpêtrière, F-75013, Paris, France isabelle.malet@psl.aphp.fr.
Isabelle
I
Malet
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, Laboratoire de Virologie, Hôpital Pité-Salpêtrière, F-75013, Paris, France.
Laura
L
Gimferrer Arriaga
Dipartimento di Scienze della Salute, Università degli Studi 'Magna Græcia', Campus 'S. Venuta', Viale Europa, Germaneto, Catanzaro 88100, Italy.
Anna
A
Artese
Dipartimento di Scienze della Salute, Università degli Studi 'Magna Græcia', Campus 'S. Venuta', Viale Europa, Germaneto, Catanzaro 88100, Italy.
Giosuè
G
Costa
Dipartimento di Scienze della Salute, Università degli Studi 'Magna Græcia', Campus 'S. Venuta', Viale Europa, Germaneto, Catanzaro 88100, Italy.
Lucia
L
Parrotta
Dipartimento di Scienze della Salute, Università degli Studi 'Magna Græcia', Campus 'S. Venuta', Viale Europa, Germaneto, Catanzaro 88100, Italy.
Stefano
S
Alcaro
LBPA, CNRS, Ecole Normale Supérieure de Cachan, 94235 Cachan, France.
Olivier
O
Delelis
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, Laboratoire de Virologie, Hôpital Pité-Salpêtrière, F-75013, Paris, France.
Ahmed
A
Tmeizeh
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, Laboratoire de Virologie, Hôpital Pité-Salpêtrière, F-75013, Paris, France.
Christine
C
Katlama
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, Laboratoire de Virologie, Hôpital Pité-Salpêtrière, F-75013, Paris, France.
Marc-Antoine
MA
Valantin
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.
Francesca
F
Ceccherini-Silberstein
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, Laboratoire de Virologie, Hôpital Pité-Salpêtrière, F-75013, Paris, France.
Vincent
V
Calvez
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, Laboratoire de Virologie, Hôpital Pité-Salpêtrière, F-75013, Paris, France.
Anne-Geneviève
AG
Marcelin
D019943:Amino Acid Substitution; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006575:Heterocyclic Compounds, 3-Ring / Q000627:therapeutic use; D006801:Humans; D009154:Mutation; D010078:Oxazines; D010879:Piperazines; D011485:Protein Binding / Q000235:genetics; D011728:Pyridones; D011760:Pyrrolidinones / Q000627:therapeutic use*; D015363:Quinolones / Q000627:therapeutic use; D000068898:Raltegravir Potassium; D017211:Treatment Failure; D000099226:Dolutegravir
D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir
binding affinity; dolutegravir; elvitegravir; phenotype; raltegravir