Recent analysis of primate lentivirus genomes indicates that lentiviruses have infected primates for hundreds of years. The pathogenicity of such viruses may fluctuate due to the high evolution rate of some parts of the viral genome. Fixed nucleic acid substitutions in the gag gene appear to be caused by random fixation of selectively neutral mutants, whereas nonrandom fixation of selectively advantageous mutants, as has been observed for MHC molecules and serine protease inhibitors, appears to be operational for some hypervariable env gene regions. The former is characterized by an excess of silent mutations independent of the rate of change, the latter by an excess of nonsilent mutations. This latter type of selection may especially characterize the third variable region of the external HIV envelope (V3), which contains the principal neutralization domain.