Fiche publication
Date publication
avril 2018
Journal
The Journal of biological chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr RUFF Marc
,
Dr KLAHOLZ Bruno
Tous les auteurs :
Bonnard D, Le Rouzic E, Eiler S, Amadori C, Orlov I, Bruneau JM, Brias J, Barbion J, Chevreuil F, Spehner D, Chasset S, Ledoussal B, Moreau F, Saïb A, Klaholz BP, Emiliani S, Ruff M, Zamborlini A, Benarous R
Lien Pubmed
Résumé
Recently, a new class of HIV-1 integrase (IN) inhibitors with a dual mode of action, called IN-LEDGF/p75 allosteric inhibitors (INLAIs), was described. Designed to interfere with the IN-LEDGF/p75 interaction during viral integration, unexpectedly, their major impact was on virus maturation. This activity has been linked to induction of aberrant IN multimerization, whereas inhibition of the IN-LEDGF/p75 interaction accounts for weaker antiretroviral effect at integration. Because these dual activities result from INLAI binding to IN at a single binding site, we expected that these activities co-evolved together, driven by the affinity for IN. Using an original INLAI, MUT-A, and its activity on an Ala-125 (A125) IN variant, we found that these two activities on A125-IN can be fully dissociated: MUT-A-induced IN multimerization and the formation of eccentric condensates in viral particles, which are responsible for inhibition of virus maturation, were lost, whereas inhibition of the IN-LEDGF/p75 interaction and consequently integration was fully retained. Hence, the mere binding of INLAI to A125 IN is insufficient to promote the conformational changes of IN required for aberrant multimerization. By analyzing the X-ray structures of MUT-A bound to the IN catalytic core domain (CCD) with or without the Ala-125 polymorphism, we discovered that the loss of IN multimerization is due to stabilization of the A125-IN variant CCD dimer, highlighting the importance of the CCD dimerization energy for IN multimerization. Our study reveals that affinity for the LEDGF/p75-binding pocket is not sufficient to induce INLAI-dependent IN multimerization and the associated inhibition of viral maturation.
Mots clés
INLAI, LEDGF, allosteric regulation, crystal structure, human immunodeficiency virus (HIV), inhibitor, integrase, multimerization, polymorphism, viral replication
Référence
J. Biol. Chem.. 2018 Apr 20;293(16):6172-6186
