Restriction of Foamy Viruses by Primate Trim5α

Abstract

Foamy viruses (FVs) are unconventional retroviruses with a replication strategy that is significantly different from orthoretroviruses and bears some homology to that of hepadnaviruses. Although some cellular proteins, such as APOBEC3, have been reported to block FVs, no restriction by Trim5␣ has been described to date. The sensitivity of three FV isolates of human-chimpanzee or prototypic (PFV), macaque (SFVmac), and feline (FFV) origin to a variety of primate Trim5␣s was therefore tested. PFV and SFVmac were restricted by Trim5␣s from most New World monkeys, but not from other primates, whereas FFV-based vectors were restricted by Trim5␣s from the great apes gorilla and orangutan. Trim5␣s from Old World monkeys did not restrict any FV isolate tested. Capuchin Trim5␣ was unique, as it restricted SFVmac and FFV but not PFV. Trim5␣ specificity for FVs was determined by the B30.2 domain, interestingly involving, in some instances, the same residues of the variable regions previously implicated as major determinants for human immunodeficiency virus type 1 restriction. FVs with chimeric Gags were made to map the viral determinants of sensitivity to restriction. The N-terminal half of the Gag molecule was found to contain the regions that control susceptibility. This region most likely corresponds to the capsid of conventional retroviruses. Due to their unique replication strategy, FVs should provide a valuable new system to examine the mechanism of retroviral restriction by Trim5␣.Foamy viruses (FVs), also known as spumaviruses, are the sole members of the Spumaretrovirinae subfamily of retroviruses. They have been isolated from a wide range of mammalian hosts, including primates, cats, cows, and horses, and are characterized in vitro by a very broad tropism, allowing the infection of a great variety of different cell types and species (reviewed in reference 32). In cell culture, FV replication often results in the formation of vacuolated, multinucleated syncytia with a characteristic foamy appearance (53). Nevertheless, they have yet to be strongly associated with any disease in vivo.FVs display a number of remarkable differences in their life cycles compared to conventional retroviruses. Interestingly, some of the unique features of the FV replication strategy show strong homology to those of hepatitis B virus. For example, unlike other members of the retrovirus family, reverse transcription of FVs occurs predominantly in producer cells, not targets. Although FV particles contain both viral RNA and DNA at a ratio of about 5:1, studies on the kinetics of reverse transcription, together with those on the rescue of infectious virus after cell transfection, strongly suggest that the functionally relevant nucleic acid within virions is DNA (36,51,70,71). Furthermore, the FV Pol protein is expressed as a separate protein instead of the Gag-Pol fusion protein found in other retroviruses (6,15,24,29,70). The FV Gag protein is unusual because it is not clearly divided and processed into matrix (MA), capsid (CA), and nucleo...

Structural basis for spumavirus GAG tethering to chromatin

“…Using α-satellite-specific quantitative PCR as an independent method, we estimated that the R540Q mutant integrated 7.8 ± 1.1 times more frequently in the vicinity of α-satellites than the WT control in HT1080 cells. Finally, to confirm that the observed phenotypes are independent of the vector construct or the original viral isolate, we studied integration site distributions of non-codon-optimized vectors based on PFV and SFV mac (32,33). Arg anchor substitution variants of either vector displayed twofold defects in the ability to transduce HT1080 cells while integrating with nearly WT efficiency (SI Appendix, Fig.…”

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

“…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).…”

“…Understanding when these adaptive changes occurred, together with how they altered the antiviral specificities of these genes, can lead to strong inferences about the existence of ancient viruses and their consequences on the modern function and specificity of the primate innate immune system. For example, although the TRIM5α protein encodes a retroviral restriction factor that blocks the viral life cycle of several retroviruses (3)(4)(5)(6)(7)(8), retroviral specificity varies among primates as a result of ancient selection for changes in antiviral specificity (9)(10)(11)(12). These species-specific differences in TRIM5α are due to dramatic variation in both the coiled-coil and B30.2 domains, which are responsible for the interaction with the viral capsid protein of a variety of retroviruses (13,14).…”

Molecular evolution of the antiretroviral TRIM5 gene

“…The precise mechanism of TRIM5α restriction is still the subject of intense scrutiny, but probably involves premature disassembly of the capsid core Perron et al 2007;Sebastian and Luban 2005;Shi and Aiken 2006;Stremlau et al 2006;Wu et al 2006). The majority of work published thus far has focused on primate orthologs of TRIM5α, and collectively, these have been reported to restrict a variety of divergent retroviral targets, including both primate and nonprimate lentiviruses, gammaretroviruses, betaretroviruses, and spumaretroviruses (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). Primate studies indicate that TRIM5α proteins have the potential to affect immunity against HIV, but like all other layers of potential human immunity to this viral pathogen, the human TRIM5 ortholog is ineffective against HIV .…”

“…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).…”