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The Journal of Immunology, 2005, 175: 3157-3164.
Copyright © 2005 by The American Association of Immunologists

HIV Nef-Mediated CD4 Down-Regulation Is Adaptor Protein Complex 2 Dependent1

Yong-Jiu Jin2,*,{ddagger}, Catherine Yi Cai*, Xiaoping Zhang{ddagger}, Hui-Tang Zhang*, John A. Hirst* and Steven J. Burakoff*,{dagger}

* Skirball Institute of Biomedical Research and {dagger} Department of Medicine, New York University School of Medicine, New York, NY 10016; and {ddagger} Department of Pharmaceutics, Rutgers University College of Pharmacy, Piscataway, NJ 08854

Nef is a crucial viral protein for HIV to replicate at high titers and in the development of AIDS. One Nef function is down-regulating CD4 from the cell surface, which correlates with Nef-enhanced viral pathogenicity. Nef down-regulates CD4 by linking CD4 to clathrin-coated pits. However, the mechanistic connection between the C-terminal dileucine motif of Nef and the component(s) of the clathrin-coated pits has not been pinpointed. In this report we used two AP-2 complex-specific inhibitors: a dominant negative mutant of Eps15 (Eps15DIII) that binds to the {alpha} subunit of AP-2 complex and a small interference RNA that is specific for the µ2 subunit of AP-2 complex. We show that both HIV Nef- and SIV Nef-mediated CD4 down-regulations were profoundly blocked by the synergistic effect of Eps15DIII and RNA interference of AP-2 expression. The results demonstrate that HIV/SIV Nef-mediated CD4 down-regulation is AP-2 dependent. We also show that the PMA-induced CD4 down-regulation was blocked by these two inhibitors. Therefore, PMA-induced CD4 down-regulation is also AP-2 dependent. The results demonstrate that, like the tyrosine sorting motif-dependent endocytosis (for which the transferrin receptor and the epidermal growth factor receptor are the two prototypes), dileucine sorting motif-dependent endocytosis of Nef and CD4 are also AP-2 dependent.




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