TRIM5α mediates the postentry block to N-tropic murine leukemia viruses in human cells

Perron, Michel; Stremlau, Matthew; Song, Byeongwoon; Ulm, Wes; Mulligan, Richard C.; Sodroski, Joseph

doi:10.1073/pnas.0403364101

Cited by 271 publications

(306 citation statements)

References 43 publications

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“…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 ).…”

Section: Introductionmentioning

confidence: 81%

“…[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.…”

Section: Introductionmentioning

confidence: 81%

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

et al. 2010

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Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 81%

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

et al. 2010

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“…TRIM5␣ is a tripartite motif protein, with RING, B-box, and coiled-coil (RBCC) domains (5). Only the longest TRIM5 isoform, TRIM5␣, possesses a C-terminal B30.2 domain and exhibits antiretroviral activity (4,(6)(7)(8)(9). Variation in TRIM5␣ protein sequences among primate species accounts for the observed patterns of speciesspecific restrictions to retrovirus infection (10,11).…”

mentioning

confidence: 99%

Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5α restriction factor

Stremlau

Perron

Lee

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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652

883

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The host restriction factor TRIM5␣ mediates species-specific, early blocks to retrovirus infection; susceptibility to these blocks is determined by viral capsid sequences. Here we demonstrate that TRIM5␣ variants from Old World monkeys specifically associate with the HIV type 1 (HIV-1) capsid and that this interaction depends on the TRIM5␣ B30.2 domain. Human and New World monkey TRIM5␣ proteins associated less efficiently with the HIV-1 capsid, accounting for the lack of restriction in cells of these species. After infection, the expression of a restricting TRIM5␣ in the target cells correlated with a decrease in the amount of particulate capsid in the cytosol. In some cases, this loss of particulate capsid was accompanied by a detectable increase in soluble capsid protein.Inhibiting the proteasome did not abrogate restriction. Thus, TRIM5␣ restricts retroviral infection by specifically recognizing the capsid and promoting its rapid, premature disassembly.

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“…The differences in N-and B-MLV infectivities are due to a single amino acid residue at position 110 (arginine and glutamic acid, respectively) in the retroviral capsid. The exact mechanism of action of Fv1 remains to be elucidated.Another retroviral restriction factor is the cytoplasmic body component TRIM5␣, a member of the tripartite motif (TRIM) family of proteins (10,14,24,33,40). As a defining feature of TRIM proteins, TRIM5␣ harbors an RBCC motif, which consists of a RING ("really interesting new gene") domain at the N terminus followed by a B box-2 domain and a coiled-coil domain (25).…”

mentioning

confidence: 99%

“…Whereas rhesus monkey TRIM5␣ has the ability to restrict human immunodeficiency virus type 1, human TRIM5␣ (huTRIM5␣) restricts N-MLV, but not B-MLV, infection (40). Interestingly, as for Fv1, the same amino acid residue at position 110 within the retroviral capsid controls susceptibility to TRIM5␣ restriction (24,36). However, although Fv1 and huTRIM5␣ seem to interact with the retroviral capsid at an early postentry step, the mechanisms of restriction appear to differ.…”

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confidence: 99%

Cellular Restriction of Retrovirus Particle-Mediated mRNA Transfer

Galla

Schambach

Towers³

et al. 2008

J Virol

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Analyzing cellular restriction mechanisms provides insight into viral replication strategies, identifies targets for antiviral drug design, and is crucial for the development of novel tools for experimental or therapeutic delivery of genetic information. We have previously shown that retroviral vector mutants that are unable to initiate reverse transcription mediate a transient expression of any sequence which replaces the gag-pol transcription unit, a process we call retrovirus particle-mediated mRNA transfer (RMT). Here, we further examined the mechanism of RMT by testing its sensitivity to cellular restriction factors and short hairpin RNAs (shRNAs). We found that both human TRIM5␣ and, to a lesser extent, Fv1 effectively restrict RMT if the RNA is delivered by a restriction-sensitive capsid. While TRIM5␣ restriction of RMT led to reduced levels of retroviral mRNA in target cells, restriction by Fv1 did not. Treatment with the proteasome inhibitor MG132 partially relieved TRIM5␣-mediated restriction of RMT. Finally, cells expressing shRNAs specifically targeting the retroviral mRNA inhibited RMT particles, but not reverse-transcribing particles. Retroviral mRNA may thus serve as a translation template if not used as a template for reverse transcription. Our data imply that retroviral nucleic acids become accessible to host factors, including ribosomes, as a result of particle remodeling during cytoplasmic trafficking.Retroviruses enter cells in a receptor-mediated manner, following which a reverse transcription (RT) complex is formed in the cytoplasm to reverse transcribe the genomic mRNA into double-stranded DNA. During the completion of RT, a hybrid virus-cellular nucleoprotein structure known as the preintegration complex (PIC) is formed. Eventually, active transport of the PIC into the nucleus or dissolution of the nuclear membrane during mitosis allows the viral integrase to integrate the viral double-stranded DNA into chromosomal cellular DNA (35). We have previously shown that retroviral vector mutants that are unable to initiate RT of their capped, plus-stranded mRNA genomes mediate a transient expression of the sequences cloned into the gag-pol-equivalent position of the vector genome (8). Particles conferring this activity required the presence of the retroviral mRNA packaging signal within the vector sequence, as well as the expression of both Gag and Env in the vector packaging cell, but not reverse transcriptase. We refer to this previously unexplored aspect of the retrovirus life cycle as retrovirus particle-mediated mRNA transfer (RMT). Using replication-defective retroviral vectors in which the gene of interest is cloned in the position of the gag reading frame, RMT can be exploited as a novel approach for the transient expression of a gene of interest (8).The analysis of cellular restriction factors that belong to the innate immune response against retroviruses may provide further insights into the mechanisms of RMT. The cellular restriction factor Fv1 (Friend virus susceptibility factor 1) h...

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TRIM5α mediates the postentry block to N-tropic murine leukemia viruses in human cells

Cited by 271 publications

References 43 publications

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

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

Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5α restriction factor

Cellular Restriction of Retrovirus Particle-Mediated mRNA Transfer

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