The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity

Abstract : AbstractBackground HIV-1 Integrase (IN) interacts with the cellular co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host genome enabling integration. Recently a new class of IN inhibitors was described, the IN-LEDGF allosteric inhibitors (INLAIs). Designed to interfere with the IN-LEDGF interaction during integration, the major impact of these inhibitors was surprisingly found on virus maturation, causing a reverse transcription defect in target cells.Results Here we describe the MUT-A compound as a genuine INLAI with an original chemical structure based on a new type of scaffold, a thiophene ring. MUT-A has all characteristics of INLAI compounds such as inhibition of IN-LEDGF/p75 interaction, IN multimerization, dual antiretroviral (ARV) activities, normal packaging of genomic viral RNA and complete Gag protein maturation. MUT-A has more potent ARV activity compared to other INLAIs previously reported, but similar profile of resistance mutations and absence of ARV activity on SIV. HIV-1 virions produced in the presence of MUT-A were non-infectious with the formation of eccentric condensates outside of the core. In studying the immunoreactivity of these non-infectious virions, we found that inactivated HIV-1 particles were captured by anti-HIV-specific neutralizing and non-neutralizing antibodies (b12, 2G12, PGT121, 4D4, 10-1074, 10E8, VRC01) with efficiencies comparable to non-treated virus. Autologous CD4+ T lymphocyte proliferation and cytokine induction by monocyte-derived dendritic cells (MDDC) pulsed either with MUT-A-inactivated HIV or non-treated HIV were also comparable.Conclusions Although strongly defective in infectivity, HIV-1 virions produced in the presence of the MUT-A INLAI have a normal protein and genomic RNA content as well as B and T cell immunoreactivities comparable to non-treated HIV-1. These inactivated viruses might form an attractive new approach in vaccine research in an attempt to study if this new type of immunogen could elicit an immune response against HIV-1 in animal models.
Type de document :
Article dans une revue
Retrovirology, BioMed Central, 2016, 14 (1), pp.50. 〈10.1186/s12977-017-0373-2〉
Liste complète des métadonnées

http://www.hal.inserm.fr/inserm-01633246
Contributeur : Bmc Bmc <>
Soumis le : dimanche 12 novembre 2017 - 06:41:04
Dernière modification le : jeudi 15 mars 2018 - 10:12:30
Document(s) archivé(s) le : mardi 13 février 2018 - 12:39:06

Fichiers

12977_2017_Article_373.pdf
Publication financée par une institution

Identifiants

Collections

Citation

Céline Amadori, Yme Ubeles Van Der Velden, Damien Bonnard, Igor Orlov, Nikki Van Bel, et al.. The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity. Retrovirology, BioMed Central, 2016, 14 (1), pp.50. 〈10.1186/s12977-017-0373-2〉. 〈inserm-01633246〉

Partager

Métriques

Consultations de la notice

62

Téléchargements de fichiers

44