Down-regulation of CTLA-4 by HIV-1 Nef protein.

Mohamed El-Far (1, 2) , Catherine Isabelle (1, 2) , Nicolas Chomont (1, 2, 3) , Martin Bourbonnière (1, 2) , Simone Fonseca (1, 2, 3) , Petronela Ancuta (1) , Yoav Peretz (1, 2) , Younes Chouikh (1, 2) , Rabih Halwani (4) , Olivier Schwartz (5) , Joaquín Madrenas (6) , Gordon J Freeman (7) , Jean-Pierre Routy (8) , Elias K Haddad (1, 2, 3) , Rafick-Pierre Sékaly (1, 2, 3)

1 Hopital Saint-Luc
2 Laboratoire d'Immunologie
3 VGTI - Vaccine and Gene Therapy Institute Florida
4 KSU - King Saud University [Riyadh]
5 CNRS-UMR3569 - Virus et Immunité - Virus and immunity
6 Department of Microbiology and Immunology [Montréal]
7 Dana-Farber Cancer Institute [Boston]
8 Montreal Chest Institute

HIV-1 Nef protein down-regulates several cell surface receptors through its interference with the cell sorting and trafficking machinery. Here we demonstrate for the first time the ability of Nef to down-regulate cell surface expression of the negative immune modulator CTLA-4. Down-regulation of CTLA-4 required the Nef motifs DD175, EE155 and LL165, all known to be involved in vesicle trafficking. Disruption of the lysosomal functions by pH-neutralizing agents prevented CTLA-4 down-regulation by Nef, demonstrating the implication of the endosomal/lysosomal compartments in this process. Confocal microscopy experiments visualized the co-localization between Nef and CTLA-4 in the early and recycling endosomes but not at the cell surface. Overall, our results provide a novel mechanism by which HIV-1 Nef interferes with the surface expression of the negative regulator of T cell activation CTLA-4. Down-regulation of CTLA-4 may contribute to the mechanisms by which HIV-1 sustains T cell activation, a critical step in viral replication and dissemination.

Domaines: Sciences du Vivant [q-bio]; Virologie

Mohamed El-Far, Catherine Isabelle, Nicolas Chomont, Martin Bourbonnière, Simone Fonseca, et al.. Down-regulation of CTLA-4 by HIV-1 Nef protein.. PLoS ONE, 2013, 8 (1), pp.e54295. ⟨10.1371/journal.pone.0054295⟩. ⟨pasteur-01109470⟩