Retrovirology (Nov 2017)

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

  • Céline Amadori,
  • Yme Ubeles van der Velden,
  • Damien Bonnard,
  • Igor Orlov,
  • Nikki van Bel,
  • Erwann Le Rouzic,
  • Laia Miralles,
  • Julie Brias,
  • Francis Chevreuil,
  • Daniele Spehner,
  • Sophie Chasset,
  • Benoit Ledoussal,
  • Luzia Mayr,
  • François Moreau,
  • Felipe García,
  • José Gatell,
  • Alessia Zamborlini,
  • Stéphane Emiliani,
  • Marc Ruff,
  • Bruno P. Klaholz,
  • Christiane Moog,
  • Ben Berkhout,
  • Montserrat Plana,
  • Richard Benarous

DOI
https://doi.org/10.1186/s12977-017-0373-2
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 17

Abstract

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Abstract Background 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.

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