Down-Regulation of CTLA-4 by HIV-1 Nef Protein

作者：El Far Mohamed; Isabelle Catherine; Chomont Nicolas; Bourbonniere Martin; Fonseca Simone; Ancuta Petronela; Peretz Yoav; Chouikh Younes; Halwani Rabih; Schwartz Olivier; Madrenas Joaquin; Freeman Gordon J; Routy Jean Pierre; Haddad Elias K; Sekaly Rafick Pierre^*

来源：PLos One, 2013, 8(1): e54295.

DOI：10.1371/journal.pone.0054295

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.

• 出版日期2013-1-23