The host restriction factor TRIM5α mediates a post-entry, pre-integration block to retroviral infection that depends upon recognition of the viral capsid by the TRIM5α PRYSPRY domain. The two predominant alleles of rhesus macaque TRIM5α (rhTRIM5αQ and rhTRIM5αTFP) restrict HIV 1, but cannot restrict the macaque-adapted virus SIVmac239. To investigate how TRIM5α recognizes retroviral capsids, we exploited the differential sensitivities of these two viruses to identify gain-of-sensitivity mutations in SIVmac239, and we solved the structure of the SIVmac239 capsid N-terminal domain. When mapped onto this structure, single amino acid substitutions affecting both alleles were in the β-hairpin. In contrast, mutations specifically affecting rhTRIM5αTFP surround a highly conserved patch of amino acids that is unique to capsids of primate lentiviruses. This "patch" sits at the junction between the binding sites of multiple cellular cofactors (cyclophilin A, Nup-358 cyclophilin A-like domain, Nup-153 and CPSF6). Differential restriction of these alleles is due to a Q/TFP polymorphism in the first variable loop (V1) within the PRYSPRY domain. Q reflects the ancestral state (present in the last common ancestor of Old World primates) and has remained unmodified in all but one lineage of African monkeys, the Cercopithecinae. While Q-alleles can be found among some Cercopithecinae primates, in others Q has been replaced by a G or overwritten by a two amino acid insertion (giving rise to TFP in macaques). In one lineage, the Q to G substitution was later followed by an adjacent 20 amino acid duplication. We found that these modifications in TRIM5α specifically impart the ability to restrict Cercopithecinae SIVs without altering β-hairpin recognition. At least twice Cercopithecinae TRIM5αs independently evolved to target the same conserved patch of amino acids in capsid. Based on these findings, we propose that the β-hairpin is a retrovirus associated molecular pattern widely exploited by TRIM5α proteins, while recognition of the cofactor binding region was driven by the emergence of the ancestors of modern Cercopithecinae SIVs. Distribution on the Cercopithecinae phylogenetic tree indicates that selection for these changes in TRIM5α V1 began 11-16 million years ago, suggesting that primate lentiviruses are at least as ancient.
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/13065027 |
| Date | 21 October 2014 |
| Creators | McCarthy, Kevin Raymond |
| Contributors | Johnson, Welkin |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Rights | open |
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