Nef Interacts with the μ Subunit of Clathrin Adaptor Complexes and Reveals a Cryptic Sorting Signal in MHC I Molecules

Abstract

The surface expression of MHC I is reduced in HIV-infected cells. We show that the Nef protein affects the intracellular sorting of HLA-A and -B molecules. In the presence of Nef, these proteins accumulate in the Golgi and colocalize with clathrin-coated vesicles. MHC I modulation relies on a tyrosine-based sorting signal located in the cytoplasmic domain of HLA-A and -B heavy chains. This cryptic sorting signal becomes operative only in the presence of Nef. Nef interacts with the medium (mu) subunit of AP adaptor complexes involved in the recognition of tyrosine-based sorting signals, likely facilitating the connection between MHC I and the clathrin-dependent sorting machinery.

Nef Stimulates Human Immunodeficiency Virus Type 1 Replication in Primary T Cells by Enhancing Virion-Associated gp120 Levels: Coreceptor-Dependent Requirement for Nef in Viral Replication

“…Nef, in contrast, is expressed immediately following infection and stimulates the internalization and degradation of CD4 molecules already present on the surface of the infected cell prior to Env and Vpu expression (2,12,59). Nef interacts simultaneously with the cytoplasmic tail of CD4 and members of the cellular clathrin endocytic machinery, such as adaptor proteins (9,19,27,30,41), ␤-cop (5,56), and/or vacuolar ATPase (42,44). Nef thus directs infected cell surface CD4 to cellular endocytic pathways and to its subsequent degradation in lysosomes.…”

Direct Priming and Cross-Priming Contribute Differentially to the Induction of CD8+ CTL Following Exposure to Vaccinia Virus Via Different Routes

“…Recently, it has been proposed that another HCMV product, UL16, serves to mask NK recognition of UL16-binding proteins or MHC class I chain-related protein B, which are ligands for the activating receptor, NKG2D/DAP10 (50). In the case of HIV-1, the Nef protein down-regulates cell surface MHC class I by accelerating the endocytosis of class I complexes (51)(52)(53)(54). The specific targeting of HLA-A and -B locus products, but not HLA-C or -E locus products, may be relevant for NK cell evasion (55).…”

Novel Cytotoxic T-Lymphocyte Escape Mutation by a Three-Amino-Acid Insertion in the Human Immunodeficiency Virus Type 1 p6 Pol and p6 Gag Late Domain Associated with Drug Resistance

“…By contrast, this individual has the HLA A*0201 allele, occurring at a high population frequency among Caucasians (28), but only one A*0201-restricted epitope was identified over the course of infection (24). These findings highlight the potential importance of HLA-C alleles in presenting HIV-1 CTL epitopes, especially since Nef-mediated down-regulation of class I molecules is less efficient on C alleles than on A and B alleles (9,21).…”