During early stages of HIV infection, the accessory protein Nef is involved in reducing the level of CD4 at the cell surface; this prevents superinfection and facilitates the release of virus progeny. Nef binds to the adaptor protein AP-2 and CD4 in clathrin-coated pits, which promotes endocytosis of CD4 and its subsequent targeting to lysosomes. Nef has also been found to interact with AP-1, but it is unknown whether this adaptor has a role in CD4 trafficking. In their work on page 429, Luis daSilva and colleagues now further examine the functional role of this interaction. Because Nef can bind to different AP-1 variants, comprising either the γ1 or the γ2 isoforms of its γ subunit, the authors specifically asked whether the two isoforms have distinct roles in Nef-mediated downregulation of CD4. Indeed, their knockdown experiments reveal that Nef requires γ2, but not γ1, for the efficient targeting of CD4 to lysosomes as γ2-depleted cells show increased localisation of CD4 to peripheral early endosomes. Depletion of γ2 also impairs the trafficking of other endocytic receptors, suggesting it might have a more general role in lysosomal targeting. Taken together, the data presented here not only provide an example for the specificity of distinct AP-1 subtypes for a particular cellular function but also define the γ2 subunit of AP-1 as a new factor for the regulation of CD4 levels during HIV infection that could be a future therapeutic target.