Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5α

Abstract

Mammalian cells express several factors that act in a cell-autonomous manner to inhibit retrovirus replication. Among these are the Friend virus susceptibility factor 1͞lentivirus susceptibility factor 1͞restriction factor 1 (Ref1) class of restriction factors, which block infection by targeting the capsids of diverse retroviruses. Here we show that lentivirus susceptibility factor 1 and Ref1 are speciesspecific variants of tripartite interaction motif 5␣ (TRIM5␣), a cytoplasmic body component recently shown to block HIV-1 infection in rhesus macaque cells, and can indeed block infection by widely divergent retroviruses. Depletion of TRIM5␣ from human cells relieved restriction of N-tropic murine leukemia virus (N-MLV), and expression of human TRIM5␣ in otherwise nonrestricting cells conferred specific resistance to N-MLV infection, indicating that TRIM5␣ is Ref1 or an essential component of Ref1. TRIM5␣ variants from humans, rhesus monkeys, and African green monkeys displayed different but overlapping restriction specificities that were quite accurately predicted by the restriction properties of the cells from which they were derived. All TRIM5␣ variants could inhibit infection by at least two different retroviruses, and African green monkey TRIM5␣ was able to inhibit infection by no less than four divergent retroviruses of human, non-human primate, equine, and murine origin. However, each TRIM5␣ variant was unable to restrict retroviruses isolated from the same species. These data indicate that TRIM5␣ can confer broad innate immunity to retrovirus infection in primate cells and is likely to be an important natural barrier to cross-species retrovirus transmission.

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

“…3 Shortly thereafter, most primates were shown to encode TRIM5a orthologues each having the capacity to restrict a particular range of retroviruses. [4][5][6][7][8][9] As would be expected, TRIM5a from a particular species does not inhibit cognate retroviruses, but it can target retroviruses from other species, thereby contributing to the prevention of inter-species transmission. 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 ).…”

“…[4][5][6][7][8][9] As would be expected, TRIM5a from a particular species does not inhibit cognate retroviruses, but it can target retroviruses from other species, thereby contributing to the prevention of inter-species transmission. 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.…”

“…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.…”

Intracellular trafficking of retroviral vectors: obstacles and advances

“…91 Ref1 and Lv1 block a different range of retroviruses, which generally exclude retroviruses normally found in the same species as the restriction factor (reviewed in Goff 73 ). The recent discovery that TRIM5a 96 underlies Ref1 and Lv1 restriction in different species [96][97][98] has made stunning progress in understanding these restriction factors.…”

Tissue-specific restriction of cyclophilin A-independent HIV-1- and SIV-derived lentiviral vectors

“…Human cells also exhibit a restriction activity called Ref1 that specifically restricts equine infectious anemia virus and N-tropic murine leukemia virus, and which was shown to be due to expression of the human TRIM5a ortholog (TRIM5a Hu ). 14 In contrast, overexpression of TRIM5a Hu only moderately restricts HIV-1 infection, and human cells are generally permissive for infection by HIV-1. 1 In addition, in human cells, the effects of CypA are opposite to those in non-human primate cells.…”