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Published online 29 November 2004. doi:10.1083/jcb.200407031
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 5, 903-913
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Article

HIV-1 Nef disrupts MHC-I trafficking by recruiting AP-1 to the MHC-I cytoplasmic tail



Jeremiah F. Roeth1, Maya Williams1, Matthew R. Kasper2, Tracey M. Filzen3, and Kathleen L. Collins1,2,3

1 Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109
2 Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109
3 Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109

Correspondence to Kathleen L. Collins: klcollin{at}umich.edu

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 µ1 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.

Abbreviations used in this paper: AP, adaptor protein; CTLs, cytotoxic T lymphocytes; endo H, endoglycosidase H; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; LAMP-1, lysosome-associated membrane protein; MHC-I, major histocompatibility complex class I molecules; MOI, multiplicity of infection; MPR, mannose 6-phosphate receptor; PACS-1, phosphofurin acidic cluster sorting protein; P/S/G, penicillin, streptomycin, and glutamine.


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