In the subset of primate lentiviruses that contain a vpu gene — HIV-1 and its simian precursors — the Nef protein has lost the ability to down-modulate CD3, block T cell activation and suppress programmed death. Vpu counteracts a host restriction factor induced by the inflammatory cytokine interferon-α. I propose that the acquisition of vpu may have allowed the viral lineage that gave rise to HIV-1 to evolve towards greater pathogenicity by removing the selective pressure for a protective Nef function that prevents damagingly high levels of immune activation.