Model of the effects of HIV-1 Nef on TCR signaling. Schematic representation of TCR signaling in presence of HIV-1 Nef. Expression of Nef down regulates cell surface exposure of the CD4 receptor. In addition, Nef strongly reduces the availability of Lck, LAT and active RAS at the plasma membrane as these components are retargeted to an intracellular compartment in their active form. This compartment represents the TGN for Lck and RAS and it is assumed here that LAT is recruited to the same compartment. Nef also localizes to these membranes; however, whether its physical presence is required for TCR rewiring remains unclear. Upon TCR stimulation, triggered F-actin remodeling is inhibited by Nef by virtue of its interaction with PAK2 (not shown). The SRC kinase Fyn, whose plasma membrane localization is unaffected by Nef, phosphorylates TCR zeta and ZAP-70, however ZAP-70 mediated phosphorylation of LAT and subsequent SLP-76 microcluster formation is potently disrupted by Nef. Presumably again through the activity of Fyn (indicated by the dotted arrow and question mark), TCR engagement also stimulates Lck-RAS at intracellular membranes, generating MAPK signaling resulting in the activation of Erk. In addition, Nef binds to IP3 receptor to induce calcium release and NFAT activation. By inducing a constitutively active intracellular Lck-RAS signaling module that is partially uncoupled from the plasma membrane, Nef tailors a narrow TCR downstream response that likely optimizes HIV-1 spread in the infected host.