HIV-1 Nef disrupts MHC-I trafficking by recruiting AP-1 to the MHC-I cytoplasmic tail.
To avoid immune recognition by cytotoxic T lymphocytes (CTLs), human immunodeficiency virus (HIV)-1 Nef disrupts the transport of major histocompatibility complex class I molecules (MHC-I) to the cell surface in HIV-infected T cells. However, the mechanism by which Nef does this is unknown. We report that Nef disrupts MHC-I trafficking by rerouting newly synthesized MHC-I from the trans-Golgi network (TGN) to lysosomal compartments for degradation. The ability of Nef to target MHC-I from the TGN to lysosomes is dependent on expression of the mu1 subunit of adaptor protein (AP) AP-1A, a cellular protein complex implicated in TGN to endolysosomal pathways. We demonstrate that in HIV-infected primary T cells, Nef promotes a physical interaction between endogenous AP-1 and MHC-I. Moreover, we present data that this interaction uses a novel AP-1 binding site that requires amino acids in the MHC-I cytoplasmic tail. In sum, our evidence suggests that binding of AP-1 to the Nef-MHC-I complex is an important step required for inhibition of antigen presentation by HIV.
Roeth
Jeremiah F
JF
Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Williams
Maya
M
Kasper
Matthew R
MR
Filzen
Tracey M
TM
Collins
Kathleen L
KL
D033961:Adaptor Protein Complex 1 / Q000378:metabolism*; D033983:Adaptor Protein Complex mu Subunits / Q000378:metabolism; D017951:Antigen Presentation / Q000276:immunology; D001665:Binding Sites / Q000276:immunology; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000821:virology; D003593:Cytoplasm / Q000276:immunology / Q000821:virology; D015693:Gene Products, nef / Q000276:immunology / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000821:virology; D008954:Models, Biological; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D054311:nef Gene Products, Human Immunodeficiency Virus; D021601:trans-Golgi Network / Q000378:metabolism / Q000821:virology
D033961:Adaptor Protein Complex 1; D033983:Adaptor Protein Complex mu Subunits; D015693:Gene Products, nef; D015395:Histocompatibility Antigens Class I; D054311:nef Gene Products, Human Immunodeficiency Virus