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J Biol Chem. 2018 Apr 20;293(16):6172-6186. doi: 10.1074/jbc.M117.816793. Epub 2018 Mar 5.

Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration.

Author information

1
From Biodim Mutabilis, 93230 Romainville, damien.bonnard@mutabilis.fr.
2
Inserm U944, CNRS UMR 7212, Université Paris Diderot, Conservatoire National des Arts et Métiers, 75010 Paris.
3
From Biodim Mutabilis, 93230 Romainville.
4
the Centre for Integrative Biology, IGBMC, Inserm, CNRS, Université de Strasbourg, 67404 Illkirch, and.
5
the Institut Cochin, Inserm U1016, 75014 Paris, France.
6
the Centre for Integrative Biology, IGBMC, Inserm, CNRS, Université de Strasbourg, 67404 Illkirch, and ruff@igbmc.fr.
7
Inserm U944, CNRS UMR 7212, Université Paris Diderot, Conservatoire National des Arts et Métiers, 75010 Paris, alessia.zamborlini@lecnam.net.
8
From Biodim Mutabilis, 93230 Romainville, benarous.r@wanadoo.fr.

Abstract

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.

KEYWORDS:

INLAI; LEDGF; allosteric regulation; crystal structure; human immunodeficiency virus (HIV); inhibitor; integrase; multimerization; polymorphism; viral replication

PMID:
29507092
PMCID:
PMC5912470
DOI:
10.1074/jbc.M117.816793
[Indexed for MEDLINE]
Free PMC Article

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