Isolation of an Active Lv1 Gene from Cattle Indicates that Tripartite Motif Protein-Mediated Innate Immunity to Retroviral Infection Is Widespread among Mammals

Abstract

Lv1/TRIM5␣ (tripartite motif 5␣) has recently emerged as an important factor influencing species-specific permissivity to retroviral infection in a range of primates, including humans. Old World monkey TRIM5␣ blocks human immunodeficiency virus type 1 (HIV-1) infectivity, and the human and New World monkey TRIM5␣ proteins are inactive against HIV-1 but active against divergent murine (N-tropic murine leukemia virus [MLV-N]) and simian (simian immunodeficiency virus from rhesus macaque [SIVmac]) retroviruses, respectively. Here we demonstrate antiviral activity of the first nonprimate TRIM protein, from cattle, active against divergent retroviruses, including HIV-1. The number of closely related human TRIM sequences makes assignment of the bovine sequence as a TRIM5␣ ortholog uncertain, and we therefore refer to it as bovine Lv1. Bovine Lv1 is closely related to primate TRIM5␣ proteins in the N-terminal RING and B-box 2 domains but significantly less homologous in the C-terminal B30.2 domain, particularly in the region shown to influence antiviral specificity. Intriguingly, some viruses restricted by bovine Lv1, including HIV-1 and MLV-N, are unable to synthesize viral DNA by reverse transcription, whereas restricted HIV-2 makes normal amounts of DNA. The data support the conclusion that TRIM protein-mediated restriction of retroviral infection is a more common attribute of mammals than previously appreciated.Retroviruses rely on host cell biology to complete their life cycle, and their success throughout mammalian evolution and their ability to jump between divergent species imply the use of conserved pathways. The identification and characterization of these host-virus interactions are expected to enable improvement in animal models of infection, including human immunodeficiency virus (HIV)-AIDS, yield novel antiviral strategies, and facilitate the use of retroviruses for therapeutic gene delivery. A successful approach has been to characterize examples of species-specific or cell-type-specific retroviral infectivity. This has revealed that, in many cases, poor infection is due to the presence of dominant inhibitors of retroviral replication, as opposed to the nonpermissive cells lacking specific activities required by the virus (3,7,10,20,34,39,40,46). Evidence for dominant antiviral factors encouraged the genetic screens that led to the discovery of the restriction factors APOBEC3G (32), tripartite motif 5␣ (TRIM5␣) (34), and TRIM-Cyp (22, 30).The prototype restriction factor is the murine Fv1 protein, which is derived from an endogenous retroviral gag sequence (5, 18). The gag-like Fv1 protein targets incoming murine leukemia virus (MLV) capsids (CAs) and blocks infection after viral DNA synthesis but before the formation of a provirus (16). There is also evidence to suggest that there may be dominant antiviral factors that restrict the late stage of the viral life cycle. The HIV-1 vpu protein has been shown to overcome a dominant block to viral egress that exists in human but not simian cells (8,43). APOBEC...

Molecular evolution of the antiretroviral TRIM5 gene

“…Alternately, other TRIM genes may be fulfilling this role in dogs (Sawyer et al 2007). In primate genomes (human, chimpanzee, and rhesus), TRIM5 is found in a cluster of four genes (TRIM6, TRIM34, TRIM5, and TRIM22), and phylogenetic analyses indicate that these four expanded from a common ancestral TRIM locus (Sawyer et al 2007;Si et al 2006;Ylinen et al 2006). At least two reports (TRIMP1) is supported by mRNA AF230412 and combines a region of the neighboring gene, TRIM34, with a region within TRIM5.…”

“…The genomes of cow, rat, and mouse contain expanded arrays of TRIM5 genes, while the human genome contains a single TRIM5 gene, and the dog genome has lost TRIM5 altogether as the result of a relatively recent gene disruption (Sawyer et al 2007;Tareen et al 2009). In addition to primate orthologs of TRIM5, antiviral activity has been reported for rabbit and cow TRIM5 genes (Schaller et al 2007;Si et al 2006;Ylinen et al 2006). So far, no antiviral activity has reported for the TRIM5 genes of mice and rats ( Fig.…”

“…Subsequent work by a number of groups demonstrated that TRIM5α from a variety of primates, including apes, Old World monkeys, and New World monkeys (Diehl et al 2008;Hatziioannou et al 2004;Keckesova et al 2004;Kono et al 2008;Saenz et al 2005;Sawyer et al 2005;Song et al 2005b;Stremlau et al 2004Stremlau et al , 2005Yap et al 2005Yap et al , 2008Ylinen et al 2005), as well as related proteins from cows (Si et al 2006;Ylinen et al 2006) and rabbits (Schaller et al 2007), have similar antiretroviral activity when tested against a variety of retroviruses. Analyses of the TRIM5α protein sequences revealed considerable interspecies divergence, with much of the variation localized to discrete subdomains in the C-terminal B30.2/SPRY domain (sometimes referred to as the SPRY or PRYSPRY domain, and referred to herein as the B30.2 domain).…”

Ovine TRIM5α Can Restrict Visna/Maedi Virus

“…This interaction, involving amino acid 332 of TRIM5␣ in humans (15) and 334 in monkeys, may explain the high relative rates of nonsynonymous changes of the primate TRIM5␣ gene (13). TRIM5␣ has been described in primates and several mammals (3,6,30,33,41) but not in sheep or goats, both of which are infected by SRLV, their own lentivirus. This study aimed to identify and characterize the ovine and caprine TRIM5␣ proteins and explore the possible restrictive role of ovine TRIM5␣ on VMV infection.…”

Recent Insights into the Mechanism and Consequences of TRIM5α Retroviral Restriction

“…3 A similar protein, TRIM-Cyp, identified in owl monkeys, also restricts HIV-1 infection. 4 Since then, TRIM5 proteins (TRIM5a and TRIMCyp) have been identified as being responsible for previously identified restrictions to retroviral infection naturally present in humans, 5,6 other primate species, 5,[7][8][9][10][11][12][13][14] cattle, 15,16 and nonprimates. 17,18 It has been shown that strong positive selective pressure has been exerted on the regions of TRIM5a proteins that confer species specificity in recognition of viral capsid determinants.…”