Evolution of cyclophilin A and TRIMCyp retrotransposition in New World primates

Abstract

Host cell factors modulate retroviral infections. Among those, cyclophilin A (CypA) promotes virus infectivity by facilitating virus uncoating or capsid unfolding or by preventing retroviral capsid interaction with cellular restriction factors. In Aotus species, a retrotransposed copy of CypA inserted into the tripartite motif 5 (TRIM5) gene encodes a fusion protein which may block human immunodeficiency virus type 1 by targeting the incoming virus to ubiquitin-ligated degradation or by interfering with normal uncoating of the incoming particle, rendering those monkeys resistant to infection. In this study, we have extensively analyzed representative specimens from all New World primate genera and shown that the retrotransposed CypA copy is only present in Aotus. We have shown that this inserted copy diverged from its original counterpart and that this occurred prior to Aotus radiation, although no positive selection was observed. Finally, our data underscores the need for a precise taxonomic identification of primate species used as models for retroviral infections and novel antiviral approaches.

FIG. 1.

PCR amplification of TRIM-CypA retrotransposition of representative New World monkey genera. Top panel, lanes: 1, Saimiri ustus; 2, Saimiri sciureus; 3, Cebus sp.; 4, Cebus sp.; 5, Cebus albifrons; 6, Cebus apella apella; 7, Cacajao melanocephalus; 8, Brachyteles arachnoides; 9, Aotus infulatus; 10, Aotus azarae boliviensis; 11, Aotus trivirgatus; 12, Aotus infulatus; 13, Aotus trivirgatus; 14, Aotus azarae; 15, Homo sapiens; 16, negative control. MW, molecular weight marker. Bottom panel, lanes: 1, Callithrix penicillata; 2, Callithrix geoffroyi; 3, Callithrix jacchus; 4, Callithrix kuhli; 5, Callithrix emiliae; 6, Callithrix argentata; 7, Callithrix humeralifer; 8, Callithrix (Cebuella) pygmaea; 9, Leontopithecus chrysopygus; 10, Leontopithecus rosalia; 11, Leontophitecus chrysomelas; 12, Saguinus fuscicollis; 13, Saguinus imperator; 14, Saguinus bicolor; 15, Alouatta seniculus; 16, Callicebus moloch; 17, Callicebus personatus; 18, Callicebus torquatus; 19, negative control.

FIG. 2.

Amino acid alignment of CypA proteins derived from sequences of original or retrotransposed CypA copies from New World monkeys (NWM) and representative species of OWP. Dots represent amino acid identities, whereas asterisks denote stop codons. Residues that are conserved among Aotus species (or NWM) are boxed in white, whereas residues which differ between the retrotransposed and the original CypA copy are boxed in gray. Residues which are known to interact with HIV-1 capsid or with cyclosporine are depicted by arrows.

FIG. 3.

Neighbor-joining nucleotide trees of New World monkey cytochrome b (A) and CypA/TRIM-CypA (B). Bootstrap values are based on 1,000 replicates. Representative species of OWP were used as outgroups.