HIV-1 Nef blocks transport of MHC class I molecules to the cell surface via a PI 3-kinase-dependent pathway.
HIV causes a chronic infection by evading immune eradication. A key element of HIV immune escape is the HIV-1 Nef protein. Nef causes a reduction in the level of cell surface major histocompatibility complex class I (MHC-I) protein expression, thus protecting HIV-infected cells from anti-HIV cytotoxic T lymphocyte (CTL) recognition and killing. Nef also reduces cell surface levels of the HIV receptor, CD4, by accelerating endocytosis. We show here that endocytosis is not required for Nef-mediated downmodulation of MHC-I molecules. The main effect of Nef is to block transport of MHC-I molecules to the cell surface, leading to accumulation in intracellular organelles. Furthermore, the effect of Nef on MHC-I molecules (but not on CD4) requires phosphoinositide 3-kinase (PI 3-kinase) activity. We propose that Nef diverts MHC-1 proteins into a PI 3-kinase-dependent transport pathway that prevents expression on the cell surface.
Swann
S A
SA
Departments of Medicine and Microbiology and Immunology, The University of Michigan, Ann Arbor, Michigan 48109, USA.
Williams
M
M
Story
C M
CM
Bobbitt
K R
KR
Fleis
R
R
Collins
K L
KL
D015153:Blotting, Western; D015704:CD4 Antigens / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation; D034281:Dynamins; D004705:Endocytosis; D005434:Flow Cytometry; D020558:GTP Phosphohydrolases / Q000378:metabolism; D015693:Gene Products, nef / Q000737:chemistry / Q000378:metabolism*; D006056:Golgi Apparatus / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D015789:HLA-A2 Antigen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D054311:nef Gene Products, Human Immunodeficiency Virus; D018909:src Homology Domains
D015704:CD4 Antigens; D002867:Chromones; D034281:Dynamins; D020558:GTP Phosphohydrolases; D015693:Gene Products, nef; D015789:HLA-A2 Antigen; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one