Host gene evolution traces the evolutionary history of ancient primate lentiviruses

Abstract

Simian immunodeficiency viruses (SIVs) have infected primate species long before human immunodeficiency virus has infected humans. Dozens of species-specific lentiviruses are found in African primate species, including two strains that have repeatedly jumped into human populations within the past century. Traditional phylogenetic approaches have grossly underestimated the age of these primate lentiviruses. Instead, here we review how selective pressures imposed by these viruses have fundamentally altered the evolutionary trajectory of hosts genes and, even in cases where there now remains no trace of the viruses themselves, these evolutionary signatures can reveal the types of viruses that were once present. Examination of selection by ancient viruses on the adaptive evolution of host genes has been used to derive minimum age estimates for modern primate lentiviruses. This type of data suggests that ancestors of modern SIV existed in simian primates more than 10 Ma. Moreover, examples of host resistance and viral adaptation have implications not only for estimating the age and host range of ancient primate lentiviruses, but also the pathogenic potential of their modern counterparts.

Keywords: human immunodeficiency virus; lentivirus; paleovirology; primates; simian immunodeficiency virus.

Figure 1.

A representative phylogeny of primate species and their lentivirus associations. The evolutionary relationship between living primate species is shown with branching orders reflecting the currently accepted species phylogeny [2]. The Old World Monkeys are subdivided into the Cercopithecinae and Colobinae subfamilies. Lentiviruses naturally associated with a given species (green in the online version) include SIVsm/SIVrcm in mangabeys, SIVmnd-1/SIVmnd-2 in mandrills, SIVagm/SIVmus in AGM/guenon, and SIVcol/SIVwrc/SIVolc in colobus monkeys. Lentiviruses arising via cross-species transmission (red in the online version) include SIVmac/SIVstm in macaques, SIVagm in baboons, SIVcpz in chimpanzees, HIV-1/HIV-2 in humans, and SIVgor in gorillas. Dashed lines depict cross-species virus transfer; lines originate from the donor species and terminate in an arrowhead at the recipient species. pSIV (blue in online version) is an endogenous primate lentivirus identified in the genomes of some lemur species. (Online version in colour.)

Figure 2.

Virus-driven evolution fuels a genetic conflict. (a) Depicted is a cycle of host–virus coevolution initiated when an antagonist encoded by a pathogenic virus counteracts a host restriction factor. Host factor variants are drawn in solid black, and viral antagonists are drawn in white. Selection of host factor variants that successfully evade antagonism is followed by counter-selection of viral variants that re-establish the host–virus interaction, applying selective pressure on the host once again, resulting in a cycle of coevolution. Note that the ‘direction’ of the arms race can be reversed, such that host antiviral effectors ‘chase’ their viral targets. (b) The age of host genetic adaptations, and consequently of the causal pathogenic viruses, can be estimated when superimposed onto the primate species phylogeny. For instance, the origins of positive selection on primate SAMHD1 appear to coincide with the birth of SAMHD1-degrading activity specific to some lentiviruses. (c) In cases where a particular restriction factor can be generally antagonized by a variety of different antagonists, information about binding sites can nevertheless delineate those amino acid changes that occurred on account of lentiviruses rather than due to antagonists encoded by other viruses (grey shading). (d) By tracing these lentiviral-specific changes on the primate phylogeny, one can infer whether one or several branches in primate phylogeny underwent selection on account of pathogenic lentiviruses. For instance, despite being antagonized by several viruses, changes in APOBEC3G required to evade lentiviral Vif can be used to calibrate Vif-escaping adaptive episodes in primate APOBEC3G. (Online version in colour.)

Figure 3.

Host heterozygosity may impede viral adaptation in the setting of cross-species transmission. (a) The outcome of experimental infection of three sabaeus AGMs that differ by A3G genotype is schematized. A3G variants are drawn as solid black bullets, whereas Vif variants are drawn as white crescents. The Vif-sensitive, ancestral A3G variant is readily antagonized by Vif. However, antagonism of the Vif-resistant, derived A3G variant requires counter-adaptation of the vif gene. Solid arrows signify in vivo evolution of vif in order to re-establish the interaction. In the ‘heterozygous’ monkey, expressing both the ancestral and derived A3G variant, vif counter-evolution does not occur. (b) Single-round virus infections were performed using virions produced in the presence of Vif and A3G. Infectivity of viruses is reported as a percentage, relative to infectivity in the absence of A3G (100%). Error bars indicate standard deviation from the mean of three infection replicates. Residues found at the Vif-binding site of the ancestral and derived A3G variants are shown in grey boxes. Red bars correspond to the parental vif encoded by the virus inoculum (SIVagm.Ver90). SIVagm.Ver90 Vif antagonizes the ancestral A3G variant, as illustrated by its ability to rescue virus infectivity (compare ‘no Vif’ with ‘parental Vif’). By contrast, SIVagm.Ver90 cannot antagonize the derived A3G variant. Vif amplified following experimental infection of a monkey homozygous for the derived A3G variant (‘adapted Vif’) demonstrates elevated antagonism of derived A3G but a loss of activity against ancestral A3G (compare ‘adapted Vif’ with ‘parental Vif’). Reversion of a cysteine residue selected in vivo (C84Y) results in Vif with the opposite specificity. (Online version in colour.)

Figure 4.

An overview of host genetic adaptations used to infer past lentivirus infections in deep and shallow time. Adaptations are described by host species, followed by the gene name, protein fusion product, of lentivirus fossil. Those marked by a vertical flag are fixed adaptations and the minimum age is anchored in the timeline. Mutations marked by a horizontal bracket are polymorphic in a single species of primate. The range of the bracket spans the minimum and maximum date at which the mutation could have appeared. ya, years ago, Myr, million years, K, thousand years. (Online version in colour.)