CD4 and infection: Whereas the ΔGY deletion within the conserved GYxxØ motif ablates endocytosis and polarized sorting, these functions were regained through novel deletions or substitutions at the expense of collateral changes in Tat and Rev. Given that SIVmac239ΔGY replicates poorly in gut CD4+ T cells and fails to infect macrophages in vivo [18,32], our findings suggest that trafficking functions, particularly the polarized sorting of Env, could be required for optimal infection of these cells, perhaps by promoting VS formation and viral spreading through cell-cell contacts.