Primate Lentivirus Capsid Sensitivity to TRIM5 Proteins

Abstract

Mammalian cells express several factors that inhibit lentiviral infection and that have been under strong selective pressure. One of these factors, TRIM5, targets the capsid protein of incoming retrovirus particles and inhibits subsequent steps of the replication cycle. By substituting human immunodeficiency virus type 1 capsid, we were able to show that a set of divergent primate lentivirus capsids was generally not susceptible to restriction by TRIM5 proteins from higher primates. TRIM5␣ proteins from other primates exhibited distinct restriction specificities for primate lentivirus capsids. Finally, we identified novel primate lentiviral capsids that are targeted by TRIMCyp proteins.Primates have been colonized by retroviruses at various times during their evolution, leading to the selection of species-specific variants of genes encoding restriction factors that defend host cells from infection. Reciprocally, in order to colonize a particular species, retroviruses have evolved resistance to these species-specific barriers by changing their protein sequences to avoid interactions with restriction factors or by expressing small proteins that specifically neutralize them. However, the specialization involved in overcoming restriction factors present in one host species can come at the expense of acquiring susceptibility to those of another. This could, in principle, limit cross-species transmission. For example, endogenous levels of the capsid (CA)-targeting restriction factor TRIM5␣ do not inhibit human immunodeficiency virus type 1 (HIV-1) replication in humans, yet rhesus TRIM5␣ is a major barrier to HIV-1 replication in rhesus macaque cells (10,12,14,20,24,32). To explore whether TRIM5␣ is a general barrier to cross-species primate lentivirus transmission, we determined the abilities of TRIM5 proteins from various primate species to restrict divergent primate lentiviruses.A limiting factor in undertaking studies of diverse primate lentiviruses is that the complete genome sequence and infectious molecular clones are not yet available for a number of these lentiviruses. Furthermore, the generation of virus isolates and infectious molecular clones often involves passage in human cells, which might lead to the selection of mutations that alter sensitivity to human restriction factors such as TRIM5␣. However, TRIM5 proteins target the viral CA pro-* Corresponding author. Mailing address:

Unique Spectrum of Activity of Prosimian TRIM5α against Exogenous and Endogenous Retroviruses

“…We have shown previously that ancestral TRIM5␣ restricted HIV-1 better than did the hominoid TRIM5␣ ancestor and human TRIM5␣ (13). Likewise, SIV strains in hominoids and Old World monkeys are resistant to host TRIM5␣ but sensitive to other simian TRIM5␣ proteins in a species-specific manner (15,25,54). In New World monkeys, TRIM5␣ mediates species-specific restriction against foamy viruses naturally found in those species (39).…”

Functional Antagonism of Rhesus Macaque and Chimpanzee BST-2 by HIV-1 Vpu Is Mediated by Cytoplasmic Domain Interactions

“…Because of this species specificity, Vpu was not predicted to support HIV-1 replication in macaques. Indeed, HIV-1 is unable to replicate in macaques, not only because of a BST-2 restriction but also because of restrictions imposed by APOBEC3G and Trim5␣ (72,73). Nevertheless, the macaque system has gained importance for HIV research and is currently the most widely used nonhuman primate model for vaccine development and the study of host immune responses.…”

Generation of human TRIM5α mutants with high HIV-1 restriction activity

“…Human TRIM5a inhibits some retroviruses, such as the equine infectious anemia virus (EIAV) and the so-called 'N strains' of the murine leukemia virus (N-MLV) 4,5,10,11 but it only weakly restricts HIV-1, HIV-2 and many simian immunodeficiency viruses (SIVs), including SIVs from macaques (SIV mac ), from African green monkeys (SIV AGM ) and from chimpanzees (SIV cpz ). 5,12,13 It is likely that the limited restriction range of TRIM5a hu has made it possible for lentiviruses infecting nonhuman primates to cross-species and thrive in humans, thus causing the current HIV pandemic. It has been suggested that TRIM5a hu derives from an ancestor gene that had evolved to provide resistance against unknown, now-extinct retroviruses, leaving us more vulnerable to infections by modern simian lentiviruses.…”