A conflict of interest: the evolutionary arms race between mammalian APOBEC3 and lentiviral Vif

Abstract

Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins are mammalian-specific cellular deaminases and have a robust ability to restrain lentivirus replication. To antagonize APOBEC3-mediated antiviral action, lentiviruses have acquired viral infectivity factor (Vif) as an accessory gene. Mammalian APOBEC3 proteins inhibit lentiviral replication by enzymatically inserting G-to-A hypermutations in the viral genome, whereas lentiviral Vif proteins degrade host APOBEC3 via the ubiquitin/proteasome-dependent pathway. Recent investigations provide evidence that lentiviral vif genes evolved to combat mammalian APOBEC3 proteins. In corollary, mammalian APOBEC3 genes are under Darwinian selective pressure to escape from antagonism by Vif. Based on these observations, it is widely accepted that lentiviral Vif and mammalian APOBEC3 have co-evolved and this concept is called an "evolutionary arms race." This review provides a comprehensive summary of current knowledge with respect to the evolutionary dynamics occurring at this pivotal host-virus interface.

Keywords: APOBEC3; Evolutionary arms race; Lentivirus; Mammal; Vif.

Fig. 1

A phylogenetic tree of lentiviral Vif. The names of the viral families (e.g., SIVgor, FIVfca and CAEV) and their strains (shown after under the bars; e.g., CP2135, TM219 and Roccaverano) are labeled on the tips. The hosts of the respective viruses are represented on the right of each branch with an illustration. The estimated CSTs and a recombination of PLVs are indicated with arrows. The circulations of FIVlru/FIVpco (in bobcats and puma) and CAEV/MVV (in goat and sheep as SRLV) in the wild are indicated with the double arrows. The scale bar indicates 0.4 amino acid substitutions per site

Fig. 2

Evolution of mammals and their A3 genes. Left A phylogenetic tree of mammals associated with lentiviruses with the geologic time (top) and age (bottom) scales is shown [14, 125]. In the phylogenetic tree, a subclass (Eutheria), a clade (Boreoeutheria), a superorder (Afrotheria), and some major orders (Primates, Rodents, Carnivora, Perissodactyla, Cetartiodactyla, Chiroptera, and Marsupialia) are labeled on each branch. Representative animals are illustrated with their common names and scientific names (in parentheses). Middle Schematics of the A3 genes in each mammal are shown. The A3 genes encoded in the CBX6-CBX7 loci of respective mammals are summarized. The name of each A3 gene is indicated on each open reading frame. Z1, Z2 and Z3 domains, which are classified by amino acid sequence, are shown in green, yellow, and blue, respectively [4]. Note that A3 genes are not encoded in the genome of opossum [115]. The “?” indicates that the number and composition of A3 genes in these mammals are currently unknown. Right The exogenous lentivirus in each mammal is shown. ND not detected (yet)

Fig. 3

CST and the evolutionary arms race between viruses and hosts. a A3 as a barrier restricting CST. The lentivirus X infects the host A, and the Vif protein of virus X antagonizes the anti-viral A3 protein of host A. a Left When the Vif of virus X antagonizes not only anti-viral A3 of host A but also that of host B, a candidate for the new host, virus X can be successfully transferred from host A to host B without anti-viral restriction mediated by A3 of host B. a Right On the other hand, if the Vif protein of virus X is unable to antagonize anti-viral A3 of host C, another candidate for the new host, the anti-viral A3 of host C plays a role in restricting the CST of virus X from host A to host C. For a successful CST, the virus X evolves to adapt to host C and its Vif acquires the ability to antagonize host C’s anti-viral A3 (“Adaptive evolution” in this panel). As a result, a nascent species virus, the virus Y, has emerged and infects host C. b The concept of an evolutionary arms race between lentiviruses (Vif) and hosts (A3). In the past, an ancestral host (the host Y) was infected with an ancestral pathogenic virus (the virus X) and an anti-viral A3 protein of host Y was antagonized by the Vif protein of virus X (1). To escape from the pathogenic infection of virus X, the host A3 acquires certain mutations to be resistant to the degradation mediated by the virus X Vif, resulting in the emergence of a novel host, the host Y′ (2). Although the anti-viral A3 of the host Y′ is resistant to the virus X Vif (3), the virus X Vif acquires mutations to adapt to the host Y′ (4). Then, a novel virus, the virus X′, emerges and its Vif is able to antagonize an anti-viral A3 of the host Y′ (5). Subsequently, similar to the process of (1) to (5), the selective pressure by the virus X′ produces the host Y″ of which A3 is resistant to the virus X′ Vif (6 and 7), while the virus X′ evolves to antagonize the host Y″ A3 and becomes the virus X″ (8 and 9). Such an “arms race” between lentiviruses and hosts has evolutionarily occurred over a long period of time (10). It is speculated that this process might trigger the duplication of A3 genes in mammals. After n-times arms races, in the present, the host Yⁿ encodes multiple anti-viral A3 proteins, while the Vif of the virus Xⁿ antagonizes them (11)