Two elements target SIV Nef to the AP-2 clathrin adaptor complex, but onlyone is required for the induction of CD4 endocytosis

The simian immunodeficiency virus (SIV) and human immunodeficiency virus ty pe 1 (HIV-1) Nef proteins induce the endocytosis of CD4 and class I MHC mol ecules. Here we show that SIV Nef interacts with the AP-2 adaptor complex v ia two elements located in the N-terminal region of the Nef molecule, but o nly the N-distal element is required to induce CD4 endocytosis, This N-dist al AP-2 targeting element contains no canonical endocytic signals and proba bly contacts the AP-2 complex via a novel interaction surface. The data sup port a model where SIV Nef induces CD4 endocytosis by promoting the normal interactions between the di-leucine sorting signal in the CD4 cytoplasmic d omain and AP-2, but does not substitute for the CD4-AP-2 adaptor interactio n. Neither element is important for the induction of class I MHC endocytosi s, thus indicating that different mechanisms underlie the induction of clas s I MHC and CD4 endocytosis by Nef, In contrast to SIV Nef, HIV-1 Nef inter acts with AP-2 via a surface containing a di-leucine endocytosis signal in the C-terminal disordered loop of Nef, The fact that genetic selection main tains similar molecular interactions via different surfaces in SIV and HIV- 1 Nef proteins indicates that these interactions have critical roles for th e viral life cycle in vivo.