4htw

Publication Abstract from PubMed

Retroviral capsid recognition by Trim5 blocks productive infection. Rhesus macaques harbor three functionally distinct Trim5 alleles: Trim5alpha(Q) , Trim5alpha(TFP) and Trim5(CypA) . Despite the high degree of amino acid identity between Trim5alpha(Q) and Trim5alpha(TFP) alleles, the Q/TFP polymorphism results in the differential restriction of some primate lentiviruses, suggesting these alleles differ in how they engage these capsids. Simian immunodeficiency virus of rhesus macaques (SIVmac) evolved to resist all three alleles. Thus, SIVmac provides a unique opportunity to study a virus in the context of the Trim5 repertoire that drove its evolution in vivo. We exploited the evolved rhesus Trim5alpha resistance of this capsid to identify gain-of-sensitivity mutations that distinguish targets between the Trim5alpha(Q) and Trim5alpha(TFP) alleles. While both alleles recognize the capsid surface, Trim5alpha(Q) and Trim5alpha(TFP) alleles differed in their ability to restrict a panel of capsid chimeras and single amino acid substitutions. When mapped onto the structure of the SIVmac239 capsid N-terminal domain, single amino acid substitutions affecting both alleles mapped to the beta-hairpin. Given that none of the substitutions affected Trim5alpha(Q) alone, and the fact that the beta-hairpin is conserved among retroviral capsids, we propose that the beta-hairpin is a molecular pattern widely exploited by Trim5alpha proteins. Mutations specifically affecting rhesus Trim5alpha(TFP) (without affecting Trim5alpha(Q) ) surround a site of conservation unique to primate lentiviruses, overlapping the CPSF6 binding site. We believe targeting this site is an evolutionary innovation driven specifically by the emergence of primate lentiviruses in Africa during the last 12 million years. This modularity in targeting may be a general feature of Trim5 evolution, permitting different regions of the PRYSPRY domain to evolve independent interactions with capsid.

Gain-of-Sensitivity Mutations in a Trim5-Resistant Primary Isolate of Pathogenic SIV Identify Two Independent Conserved Determinants of Trim5alpha Specificity.,McCarthy KR, Schmidt AG, Kirmaier A, Wyand AL, Newman RM, Johnson WE PLoS Pathog. 2013 May;9(5):e1003352. doi: 10.1371/journal.ppat.1003352. Epub 2013, May 9. PMID:23675300^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.