More than a decade ago it was established that intact nef genes are critical for efficient viral persistence and greatly accelerate disease progression in SIVmac-infected rhesus macaques and in HIV-1-infected humans. Subsequent studies established a striking number of Nef functions that evidently contribute to the maintenance of high viral loads associated with the development of immunodeficiency in the 'evolutionary-recent' human and the experimental macaque hosts. Recent data show that many Nef activities are conserved across different lineages of HIV and SIV. However, some differences also exist. For example, Nef alleles from most SIVs that do not cause disease in their natural monkey hosts, but not those of HIV-1 and its simian precursors, down-modulate TCR-CD3 to suppress T cell activation and programmed death. This evolutionary loss of a specific Nef function may contribute to the high virulence of HIV-1 in humans.