restriction factors are implicated in long-term evolutionary "arms races," in which viral antagonists drive the evolution of host proteins, and vice versa. consequently, restriction factors are remarkably variable, displaying polymorphism within species and divergence between species as a result of positive selection. this paper investigates diversity in the apobec3f (a3f) restriction factors of old world primates in order to determine whether they display evidence of involvement in an evolutionary "arms race." we speculated that genetic variability in a3f could reflect evolutionary conflict with the vif proteins of primate lentiviruses, which are known to enhance viral replication by binding and degrading host a3 proteins. a3fs of several old world primate species were genotyped, and the sequences revealed both intra-species diversity and inter-species divergence. representative rhesus macaque (macaca mulatta) sequences were cloned and tested for sensitivity to vifs from various simian immunodeficiency viruses (sivs). evolution of a3f in the rhesus lineage is not due to selection by sivs, but may reflect antagonism by another retrovirus. 1 The causative agent was soon discovered to be a lentivirus, classified as Human Immunodeficiency Virus Type 1 (HIV-1).2,3 HIV-1 and its close relative HIV Type 2 (HIV-2) arose in human populations as a result of cross-species transmission events from natural simian hosts of the Simian Immunodeficiency Viruses (SIVs). The closest simian relative of HIV-1 is the strain naturally infecting chimpanzees (SIVcpz), 4 while the closest simian relative of HIV-2 is the strain naturally infecting sooty mangabeys (SIVsm).5 Over 40 species-specific SIVs have since been identified in nonhuman primate species. A fraction of these infections result in immunodeficiency in the host species, while most are nonpathogenic in their natural hosts. 6 The SIV of a given primate species cannot readily infect a different species without undergoing numerous adaptations. Part of this adaptation process involves evading host antiviral proteins known as restriction factors. Restriction factors are host proteins that utilize numerous mechanisms to interfere with viral infections as part of the innate immune response. Some interact directly with viral factors, while others make the cellular environment unsuitable for sustained viral replication.7 These defensive genes are subject to relatively rapid evolution under the selective pressure of viral counter-restriction mechanisms, and variants that confer greater fitness to the host during a viral outbreak will become fixed in a population much faster than would normally be expected as a result of genetic drift alone. The virus, in turn, can adapt to infect the host carrying these more fit alleles, creating a new selective pressure on the host. Thus, over evolutionary time, a comparatively large number of non-synonymous, or protein-altering, mutations will be evident in genes that have participated in these virus-host "arms races." 8 Genes can be examined for e...