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

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

Abstract : 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.

Author: Mohamed El-Far - Catherine Isabelle - Nicolas Chomont - Martin Bourbonnière - Simone Fonseca - Petronela Ancuta - Yoav Peretz -



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