Variable Prevalence and Functional Diversity of the Antiretroviral Restriction Factor TRIMCyp in Macaca fascicularis

Abstract

The retroviral restriction factor TRIMCyp, derived from the TRIM5 gene, blocks replication at a postentry step. TRIMCyp has so far been found in four species of Asian macaques, Macaca fascicularis, M. mulatta, M. nemestrina, and M. leonina. M. fascicularis is commonly used as a model for AIDS research, but TRIMCyp has not been analyzed in detail in this species. We analyzed the prevalence of TRIMCyp in samples from Indonesia, Indochina, the Philippines, and Mauritius. We found that TRIMCyp is present at a higher frequency in Indonesian than in Indochinese M. fascicularis macaques and is also present in samples from the Philippines. TRIMCyp is absent in Mauritian M. fascicularis macaques. We then analyzed the restriction specificity of TRIMCyp derived from three animals of Indonesian origin. One allele, like the prototypic TRIMCyp alleles described for M. mulatta and M. nemestrina, restricts human immunodeficiency virus type 2 (HIV-2) and feline immunodeficiency virus (FIV) but not HIV-1. The others restrict HIV-1 and FIV but not HIV-2. Mutagenesis studies confirmed that polymorphisms at amino acid residues 369 and 446 in TRIMCyp (or residues 66 and 143 in the cyclophilin A [CypA] domain) confer restriction specificity. Additionally, we identified a polymorphism in the coiled-coil domain that appears to affect TRIMCyp expression or stability. Taken together, these data show that M. fascicularis has the most diverse array of TRIM5 restriction factors described for any primate species to date. These findings are relevant to our understanding of the evolution of retroviral restriction factors and the use of M. fascicularis models in AIDS research.Primates express several intrinsic restriction factors that can combat retroviral infection (15). One of the best studied is TRIM5␣, which binds to the retroviral capsid and restricts replication at a postentry step (31). TRIM5␣ belongs to the TRIM (tripartite motif) gene family, a large family found throughout vertebrates with numerous members that have been implicated in immune responses (20,24). TRIM genes contain, in order, RING, B-box, and coiled-coil domains (23). TRIM5␣ also has a C-terminal B30.2/SPRY domain, which is required for binding to retroviral capsids (27,32).In some primates, the retrotransposition of a cyclophilin A (CypA) sequence into the TRIM5 gene allows the expression of the TRIMCyp isoform. Alternative splicing to this insertion results in the replacement of the capsid-binding B30.2/SPRY domain with a CypA domain, which is also capable of binding some retroviral capsids (14). Thus, TRIMCyp, like TRIM5␣, has retroviral restriction activity, but its specificity is determined by the CypA domain rather than the B30.2/SPRY domain. Interestingly, TRIMCyp has evolved independently by separate retrotransposition events in two distantly related primate genera, Aotus (owl monkeys; New World monkeys), and Macaca (macaques; Old World monkeys) (2,11,18,25,36,37).In macaques, the CypA insertion is linked to a single-nucleotide polymorphism (SNP) at the exon 7 spl...

Animal models for HIV/AIDS research

“…Furthermore, the TRIM5 genes of cynomolgus macaques are also the most diverse of any primate species characterized thus far, encoding polymorphisms in both the TRIM5α and TRIMCyp isoforms, including TRIMCyp proteins that differentially restrict HIV-1 (REF. 105) (FIG. 3).…”

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

“…Previous studies have explored the interactions between CypA genes and retrogenes with lentiviral capsids (15,(24)(25)(26)(27)(32)(33)(34). We were therefore interested in assessing whether ancient, potentially active versions of TRIMCyA3 might have interacted with lentiviral capsids.…”

Host gene evolution traces the evolutionary history of ancient primate lentiviruses

“…Rhesus macaques (Macaca mulatta) encode a TRIM-CypA fusion protein that emerged in the ancestor of macaque species 5-6 Ma [50][51][52]. While rhesus TRIM5a potently blocks HIV-1 replication, TRIMCypA exhibits specificity towards HIV-2 and SIVagm, suggesting that it was selected millions of years ago in response to a lentivirus with similar characteristics [53,54]. In a remarkable demonstration of convergent evolution, a TRIMCypA fusion has evolved independently in owl monkeys (Aotus), a genus endemic to South America, establishing that the species of the New World may have been subjected to lentiviruses as well [55,56].…”