HIV‐1 down‐regulates the expression of CD1d via Nef

HIV‐1 has evolved several strategies to subvert host immune responses to the infected cells. One is to inhibit CTL recognition by HIV‐1 Nef‐mediated down‐regulation of MHC‐I expression on the surface of infected cells. Here we report that Nef also reduces the expression of the non‐classical MHC‐I like CD1d molecule, a third lineage of antigen‐presenting molecule, which presents lipid antigens. Nef achieves this by increasing internalization of CD1d molecules from the cell surface and retaining CD1d in the trans‐Golgi‐network (TGN). This effect depends on a tyrosine‐based motif present in CD1 cytoplasmic tail as well as the actions of four Nef motifs, which are known to be involved in the down‐regulation of MHC‐I or CD4. These results suggest that Nef regulates intracellular trafficking of CD1d via a distinct but shared pathway with MHC‐I and CD4. Thus, HIV‐1 reduces the visibility of its infected cells not only to MHC‐I‐restricted T cells but also to CD1d‐restricted NKT cells. Given that CD1d‐restricted T cells have unique effector and regulatory functions in innate and adapted immune responses as compared with their counterpart MHC‐restricted T cells, our data provide additional new insights into molecular basis of HIV‐1‐mediated damage to the immune system.