APOBEC3 (apolipoprotein B mRNA editing catalytic polypeptide 3 [A3]) proteins are an element of the intrinsic immunity of modern mammalia against retroviruses. The evolution of the A3 genes is characterized by an adaptive selection and a taxon-specific expansion and/or extinction. All A3 genes consist either of one zinc (Z)-coordinating domain (Z1, Z2 or Z3) or two Z-domains (Z2-Z1, Z2-Z2, Z2-Z3). While humans carry seven A3 genes, Equus caballus carries six and Felis catus four A3 genes. The genome of Equus caballus carries two Z1, two Z2-Z2, one Z2 and one Z3 A3 gene. Some of the equine A3 are able to restrict the Equine infectious anaemia virus (EIAV). Equine macrophages, which are the natural target cells for EIAV, express only a limited repertoire of the A3 genes. In addition, the transcriptional level of the anti-EIAV A3 mRNAs was significantly lower in macrophages than in equine peripheral blood mononuclear cells. Equine A3 proteins hyper-mutated EIAV genomes supporting their predicted function. In contrast to all other extant lentiviruses, EIAV does not encode a vif gene. Other EIAV-specific genes as dUTPase and S2, whose relevance for the viral replication in previous studies was only insufficiently characterized, did not influence the inhibitory effect of the equine A3 proteins. Thus, EIAV does not have an antagonist against its species-own A3 proteins. These findings indicate that lentiviral replication can occur independent from a vif gene, which likely developed later in the evolution of the lentiviruses. Felis catus and of other Felidae encode A3 genes of the type Z2 and Z3. Beside one-domain molecules, also two-domain encoding read-through transcripts with two Vif interaction sites were detectable, that restricted different feline retroviruses. FIV (Feline immunodeficiency virus) encodes a Vif protein that counteracts the inhibitory effect of the feline A3 proteins. Despite a high genetic diversity in felid A3 genes, no strong resistance could be shown against the neutralizing activity of Vif of the domestic cat FIV. Non-feline A3 proteins restricted FIV independently of Vif, which proves that the interaction between A3 and Vif proteins is species-specific and thus limits interspecies virus transmission. Species-specificity was also demonstrated for the interaction of feline A3 and the Vif protein of HIV-1. Feline cells that expressed human entry receptors were permissive for the transduction with a HIV-1 reporter virus but the virus was not able to spread in these cells. HIV replication in feline cells is strongly inhibited by the feline A3 proteins. In order to overcome this restriction, the vif gene of HIV-1 was replaced by vifFIV. This chimeric HIV-1 showed spreading replication in feline cells expressing human receptors. Altogether, these findings implicate the importance of a novel animal model for HIV-1 based on Felis catus
