Independent evolution of an antiviral TRIMCyp in rhesus macaques

Abstract

The antiretroviral restriction factor TRIM5 has recently emerged as an important mediator of innate immunity and species-specific inhibition of retroviral replication in mammals. Selection pressure from pathogenic infection has driven rapid evolution of TRIM5 genes, leading to the antiviral specificities we see today. Remarkably, the New World owl monkey (Aotus trivirgatus) encodes a TRIM5 protein in which the antiviral determinants in the B30.2 domain have been replaced by cyclophilin A (CypA) encoded by a retrotransposed cDNA. The owl monkey TRIMCyp protein restricts infection by a subset of lentiviruses that recruit CypA to their capsids, including HIV-1 and feline immunodeficiency virus. Here, we show that the Old World monkey, rhesus macaque (Macaca mulatta), also encodes a TRIMCyp protein that has arisen independently from that in owl monkeys. The rhesus TRIMCyp is encoded by a single, but common, allele (Mamu7) of the rhesus TRIM5 gene, among at least six further alleles that encode full-length TRIM5 proteins with no homology to CypA. The antiviral specificity of the rhesus TRIMCyp is distinct, restricting infection of HIV-2 and feline immunodeficiency virus but not HIV-1. Restriction by rhesus TRIMCyp is before reverse transcription and inhibited by blocking CypA binding, with cyclosporine A, or by mutation of the capsid CypA binding site. These observations suggest a mechanism of restriction that is conserved between TRIMCyp proteins. The lack of activity against HIV-1 suggests that Mamu7 homozygous animals will be null for TRIM5-mediated restriction of HIV-1 and could contribute to improved animal models for HIV/AIDS. cyclophilin ͉ lentivirus ͉ restriction ͉ TRIM5 ͉ zoonosis T RIM5 has recently been identified as a powerful restriction factor responsible for species-specific restriction of retroviral infectivity as part of the innate immune system (1-6). TRIM5 has a tripartite, or RBCC, motif consisting of RING, B Box 2, and coiled coil domains with the characteristic ordering and spacing that defines the TRIM family. Together with many other members of the TRIM family, TRIM5 has a C-terminal PRY/SPRY, or B30.2, domain. In the case of TRIM5, this domain defines antiviral specificity, probably by interacting directly with the incoming viral capsid (7-13). Antiretroviral TRIM5 variants have been described in primates, cattle, and rabbits (1-3, 14-16). These TRIM5 sequences form a monophyletic group, indicating that they are derived from a common ancestor that probably had antiviral properties (16). TRIM5 blocks retroviral infectivity by an incompletely characterized mechanism that involves the proteasome (6, 17, 18) and may involve capsid uncoating (13,19). In the New World owl monkey, the TRIM5 locus has been modified by insertion of a cyclophilin A (CypA) cDNA by retrotransposition into the seventh intron (20, 21), leading to the expression of a TRIM5 variant (TRIMCyp), in which CypA replaces the exon eight-encoded B30.2 domain. This change effectively replaces the antiviral specificity determinant, wi...

Chance favors a prepared genome

“…1 A). A SNP inactivating the exon 7 splice acceptor cosegregates with the retrotransposed CypA sequences in Trim5CypA2 (8,11), presumably resulting in increased splicing to CypA. However, we cannot be certain whether this SNP occurred before or after CypA insertion.…”

“…It was present, in homozygous form, in Ͼ20 pig-tailed macaques and in both of the cynomolgus macaques examined. By contrast, it represents one of seven Trim5 alleles found in rhesus macaques (8,14). Interestingly, it appears to be present in Indian (allele frequency 25%) but absent in Chinese rhesus macaques (8).…”

“…By contrast, it represents one of seven Trim5 alleles found in rhesus macaques (8,14). Interestingly, it appears to be present in Indian (allele frequency 25%) but absent in Chinese rhesus macaques (8). The inheritance of Trim5CypA2 might prove a useful tool for examining unresolved issues regarding the evolution of different macaque species (15).…”

“…It is therefore possible that macaques in which Trim5CypA2 has replaced TRIM5␣ might provide useful systems for studies involving HIV-1 growth. However, Trim5CypA2 clearly has restriction activity because it can block infection by HIV-2, simian immunodeficiency virus (SIV) AGM tan, and feline immunodeficiency virus (FIV) (8,9). This difference in restriction properties results from a point mutation leading to an H69R change in the CypA domain (Fig.…”

“…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.…”