Foamy viruses are a family of complex retroviruses that establish common, 
productive infections in a wide range of nonhuman primates. In contrast, humans 
appear nonpermissive for foamy virus replication, although zoonotic infections 
do occur. Here we have analyzed the ability of primate and mouse APOBEC3G 
proteins to inhibit the infectivity of primate foamy virus (PFV) virions 
produced in their presence. We demonstrate that several APOBEC3 proteins can 
potently inhibit the infectivity of a PFV-based viral vector. This inhibition 
correlated with the packaging of inhibitory APOBEC3 proteins into PFV virions, 
due to a specific PFV Gag/APOBEC3 interaction, and resulted in the G to A 
hypermutation of PFV reverse transcripts. While inhibition of PFV virion 
infectivity by primate APOBEC3 proteins was largely relieved by coexpression of 
the PFV Bet protein, a cytoplasmic auxiliary protein of previously uncertain 
function, Bet failed to relieve inhibition caused by murine APOBEC3. PFV Bet 
bound to human, but not mouse, APOBEC3 proteins in coexpressing cells, and this 
binding correlated with the specific inhibition of their incorporation into PFV 
virions. Of note, both PFV Bet and a second Bet protein, derived from an African 
green monkey foamy virus, rescued the infectivity of Vif-deficient human 
immunodeficiency virus type 1 (HIV-1) virions produced in the presence of 
African green monkey APOBEC3G and blocked the incorporation of this host factor 
into HIV-1 virion particles. However, neither foamy virus Bet protein reduced 
APOBEC3 protein expression levels in virion producer cells. While these data 
identify the foamy virus Bet protein as a functional ortholog of the HIV-1 Vif 
auxiliary protein, they also indicate that Vif and Bet block APOBEC3 protein 
function by distinct mechanisms.