TRIMCyp expression in Old World primates Macaca nemestrina and Macaca fascicularis

Abstract

Primates have evolved a variety of restriction factors that prevent retroviral replication. One such factor, TRIM5␣, mediates a postentry restriction in many Old World primates. Among New World primates, Aotus trivirgatus exerts a similar early restriction mediated by TRIMCyp, a TRIM5-cyclophilin A (CypA) chimera resulting from a CypA retrotransposition between exons 7 and 8 of the TRIM5 gene. convergent evolution ͉ cyclophilin A ͉ HIV ͉ retroviruses ͉ TRIM5␣ T he current HIV pandemic resulting from cross-species transmissions of simian immunodeficiency viruses SIVcpz or SIVsmm to humans has been well documented (1). However, the mechanisms enabling such transmissions are not yet fully understood. Mammals have evolved several restriction factors capable of inhibiting the replication of certain retroviruses in a species-specific manner. One of the best described primate host-restriction factors is TRIM5␣, which is expressed in most Old World primates.Macaca mulatta TRIM5␣ exerts an early, postentry block to HIV-1 replication (2). TRIM5␣ is a member of the tripartite motif family of proteins, characterized by the ordered Nterminal to C-terminal expression of a RING domain, B-Box, and coiled coil, also known as an RBCC domain (3). The TRIM5␣ isoform also expresses a B30.2 domain at the C terminus, which is required for recognition of the incoming retroviral capsid (4-7). Changes to the B30.2 domain have been shown to dramatically affect the breadth and potency of TRIM5␣-mediated anti-retroviral activity. For instance, the ability to restrict HIV-1 replication may be conferred to Homo sapiens TRIM5␣ by changing a single residue to the amino acid found in M. mulatta TRIM5␣, R332P (8). Similarly, site-directed mutagenesis studies have demonstrated that mutations around the cyclophilin A (CypA) binding loop of HIV-1 capsid effect the potency of TRIM5␣-mediated restriction, suggesting that the B30.2 domain interacts with or near the CypA binding loop (5, 9, 10).New World primates Aotus trivirgatus exert a postentry restriction to HIV-1 mediated by a TRIM5-CypA chimera. Sequencing the A. trivirgatus TRIM5 gene identified a LINE-1-mediated retrotransposition of CypA into intron 7, resulting in the expression of a fusion protein called TRIMCyp, which is unique to the Aotus genus (11-13). TRIMCyp retains the N-terminal tripartite motif of all TRIM family members, but the B30.2 domain of TRIM5␣ is replaced by the CypA domain. Functionally, TRIM5␣ and TRIMCyp are similar, preventing reverse transcription of incoming viruses at an early postentry stage. However, TRIMCyp exerts a more potent restriction to incoming retroviruses than TRIM5␣, and unlike TRIM5␣, TRIMCyp-mediated restriction is sensitive to cyclosporin A. A. trivirgatus has been shown to express only TRIMCyp,.We recently demonstrated that the Old World primates Macaca nemestrina do not express TRIM5␣. Instead, they transcribe novel isoforms TRIM5 and TRIM5 (14). These isoforms likely arise because of a single-nucleotide polymorphism (SNP) at the intron 6 splice acc...

Birth, decay, and reconstruction of an ancient TRIMCyp gene fusion in primate genomes

“…1A and Fig. S1), is the polymorphic CypA2 identified in previous studies (24)(25)(26)(27)29) but missing from the reference rhesus macaque genome. We discovered another CypA, located ∼14 kb downstream of TRIM5, which we labeled as CypA3 (Fig.…”

“…This event is also estimated to have occurred [5][6]. Unlike CypA1 in owl monkeys, the CypA2-encoding TRIM5 allele is found at varying frequencies across macaque species (24,25,27,28). These two TRIMCyp gene fusions thus represent a remarkable case of convergent evolution in the generation of novel antiviral specificity in the TRIM5 locus.…”

“…Several macaque species also encode TRIMCyp, which is the consequence of another, independent CypA retrotransposition (CypA2 retrogene) downstream of the TRIM5 gene (24)(25)(26)(27). This event is also estimated to have occurred [5][6].…”

Chance favors a prepared genome

“…This second chimeric gene, which we will refer to as Trim5CypA2, was identified in three different species of macaque monkeys, Macaca mulatta (rhesus macaque) (8,11), Macaca nemestrina (pig-tailed macaque) (9)(10)(11)(12), and Macaca fascicularis (long-tailed or crabeating or cynomolgus macaque) (10). Like Trim5CypA1 from Aotus, Trim5CypA2 appears to have been generated by LINE element-mediated insertion (13) of a CypA pseudogene within the TRIM5 locus.…”

“…Remarkably, it now appears that the owl monkey fusion protein is not unique. Three articles in this issue of PNAS, by Wilson et al (8), Virgen et al (9), and Brennan et al (10), and two articles published elsewhere (11,12) provide a description of the second, independent case of the generation of a Trim5CypA fusion protein.…”