Abstract
The widespread distribution of lentiviruses among African primates, and the lack of severe pathogenesis in many of these natural reservoirs, are taken as evidence for long-term co-evolution between the simian immunodeficiency viruses (SIVs) and their primate hosts. Evidence for positive selection acting on antiviral restriction factors is consistent with virus-host interactions spanning millions of years of primate evolution. However, many restriction mechanisms are not virus-specific, and selection cannot be unambiguously attributed to any one type of virus. We hypothesized that the restriction factor TRIM5, because of its unique specificity for retrovirus capsids, should accumulate adaptive changes in a virus-specific fashion, and therefore, that phylogenetic reconstruction of TRIM5 evolution in African primates should reveal selection by lentiviruses closely related to modern SIVs. We analyzed complete TRIM5 coding sequences of 22 Old World primates and identified a tightly-spaced cluster of branch-specific adaptions appearing in the Cercopithecinae lineage after divergence from the Colobinae around 16 million years ago. Functional assays of both extant TRIM5 orthologs and reconstructed ancestral TRIM5 proteins revealed that this cluster of adaptations in TRIM5 specifically resulted in the ability to restrict Cercopithecine lentiviruses, but had no effect (positive or negative) on restriction of other retroviruses, including lentiviruses of non-Cercopithecine primates. The correlation between lineage-specific adaptations and ability to restrict viruses endemic to the same hosts supports the hypothesis that lentiviruses closely related to modern SIVs were present in Africa and infecting the ancestors of Cercopithecine primates as far back as 16 million years ago, and provides insight into the evolution of TRIM5 specificity.
Highlights
The lentiviruses comprise a genus within the family Retroviridae [1]
To investigate the prehistoric origins of these lentiviruses, we looked for patterns of evolution in the antiviral host gene TRIM5 that would reflect selection by lentiviruses during evolution of African primates
We identified a pattern of adaptive changes unique to the TRIM5 proteins of a subset of African monkeys that suggests that the ancestors of these viruses emerged between 11–16 million years ago, and by reconstructing and comparing the function of ancestral TRIM5 proteins with extant TRIM5 proteins, we confirmed that these adaptations confer specificity for their modern descendants, the simian immunodeficiency viruses (SIVs)
Summary
The lentiviruses comprise a genus within the family Retroviridae [1]. These include viruses of horses, small ruminants, cows and felids, as well as some 40 or more species of primate lentiviruses- the latter including HIV-1, HIV-2 and the simian immunodeficiency viruses (SIVs) of Old World African primates [2]. Endogenous sequences related to the modern lentiviruses have been discovered in the genomes of mustelids (weasels and ferrets) [4, 5], lagomorphs (rabbits and hares) [6, 7], colugos (flying lemurs) [8] and multiple species of lemur [9, 10] These ancient lentivirus ERVs (endogenous retroviruses) interleave with modern lentiviruses in phylogenetic trees, and molecular clock analyses indicate that they range in age from 3 to 12 million years [3]. The pSIVgml ERV of lemurs, shares features with both non-primate and primate lentiviruses, and represents a transitional form bridging the primate and non-primate lentiviruses [3, 9] These observations indicate that lentiviruses very similar to modern lentiviruses have existed for at least several million years. It remains an open question as to when the common ancestors of the modern primate lentiviruses first emerged in the ancestors of extant African primates, and whether emergence of these viruses influenced evolution of host antiviral defense genes
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