Down-regulation of CTLA-4 by HIV-1 Nef protein.
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.
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc, Montréal, Québec, Canada.
Mohamed
M
El-Far
Catherine
C
Isabelle
Nicolas
N
Chomont
Martin
M
Bourbonnière
Simone
S
Fonseca
Petronela
P
Ancuta
Yoav
Y
Peretz
Younes
Y
Chouikh
Rabih
R
Halwani
Olivier
O
Schwartz
Joaquín
J
Madrenas
Gordon J
GJ
Freeman
Jean-Pierre
JP
Routy
Elias K
EK
Haddad
Rafick-Pierre
RP
Sékaly
D020816:Amino Acid Motifs; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics*; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D015704:CD4 Antigens; D060908:CTLA-4 Antigen; D011993:Recombinant Fusion Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1