The Nef protein of lentiviruses is a multifunctional protein involved in viral replication, immune evasion, and modulation of lymphocyte activation. It is considered the most important virulence factor of primate and human lentiviruses. Although the nef gene is conserved among SIVs and HIVs, only HIV-1 is highly virulent in its natural host. During the course of HIV-1 infection, the functions of Nef are modulated according to host environment. The ability of the Nef protein to down-regulate MHC class I and CD4 has been found to increase since the 1980s among North American patients. Comparison of Nef proteins from SIVcpz and HIV-1 indicates that after the virus crossed hosts from chimpanzee to human, Nef lost some of its potency to down-regulate CD28. There was also a loss of the ability of Nef to down-regulate TCR-CD3 before HIV-1 entered mankind. Down-regulation of CD3 and CD28 seem to affect the balance of the virus-host relationship. Loss of these functions, along with optimization of Nef to enhance viral replication in the new host species, has been selectively favored, resulting in short-term adaptation. It is suggested that this is a primary reason for the deadly nature of HIV-1 and the tragic AIDS pandemic in the human population.