The human and African green monkey TRIM5α genes encode Ref1 and Lv1 retroviral restriction factor activities

Keckesova, Zuzana; Ylinen, Laura M. J.; Towers, Greg J.

doi:10.1073/pnas.0402474101

Cited by 321 publications

(358 citation statements)

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“…[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: 99%

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

et al. 2010

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Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…Additionally, rhTRIM5␣ and agmTRIM5␣ as well as the human variant of TRIM5␣ (huTRIM5␣) were subsequently identified as the factors responsible for restricting the infection by N-tropic MLV in cell lines derived from these species (Hatziioannou et al, 2004;Keckesova et al, 2004;Yap et al, 2004;Song et al, 2005c).…”

Section: Introductionmentioning

confidence: 99%

TRIM5α Cytoplasmic Bodies Are Highly Dynamic Structures

Campbell

Dodding

Yap

et al. 2007

MBoC

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Tripartite motif (TRIM)5␣ has recently been identified as a host restriction factor that has the ability to block infection by certain retroviruses in a species-dependent manner. One interesting feature of this protein is that it is localized in distinct cytoplasmic clusters designated as cytoplasmic bodies. The potential role of these cytoplasmic bodies in TRIM5␣ function remains to be defined. By using fluorescent fusion proteins and live cell microscopy, we studied the localization and dynamics of TRIM5␣ cytoplasmic bodies. This analysis reveals that cytoplasmic bodies are highly mobile, exhibiting both short saltatory movements and unidirectional long-distance movements along the microtubule network. The morphology of the cytoplasmic bodies is also dynamic. Finally, photobleaching and photoactivation analysis reveals that the TRIM5␣ protein present in the cytoplasmic bodies is very dynamic, rapidly exchanging between cytoplasmic bodies and a more diffuse cytoplasmic population. Therefore, TRIM5␣ cytoplasmic bodies are dynamic structures more consistent with a role in function or regulation rather than protein aggregates or inclusion bodies that represent dead-end static structures. INTRODUCTIONThe species-specific tropism of many retroviruses is determined by cellular restriction factors present in the cells of the host. One of the most well characterized restriction factors is the murine Fv1 gene, which prevents infection by particular strains of murine leukemia virus (MLV) (Best et al., 1996; for review, see Bieniasz, 2004;Goff, 2004). It is known that restriction by Fv1 involves the recognition of a capsid determinant in MLV (DesGroseillers et al., 1983;Kozak and Chakraborti, 1996). Analysis of Fv1 restriction indicates that restricted MLV strains can generate reverse transcription products but that they are unable to complete subsequent steps in infection (Pryciak and Varmus, 1992) and also that this restriction of infection is saturable, because it can be overcome with high levels of virus (Pincus et al., 1975;Duran-Troise et al., 1977).A similar restriction to human immunodeficiency virus 1 (HIV-1) infection in primates has also been well characterized; and recently, the cellular factor present in the cells of Old World monkeys responsible for restricting infection by HIV-1 was cloned and identified as the cytoplasmic body component tripartite motif (TRIM)5␣ . Restriction of HIV-1 infection by TRIM5␣ resembles restriction of MLV infection by Fv1 in many ways. TRIM5␣-mediated restriction is saturable with high multiplicity of infection (MOI), and the specificity of TRIM5␣-mediated HIV-1 restriction is governed by the recognition of a capsid determinant in the restricted virus similar to the case of Fv1-mediated restriction of MLV infection (Towers et al., 2000;Cowan et al., 2002;Owens et al., 2003Owens et al., , 2004Hatziioannou et al., 2004). However, TRIM5␣-mediated restriction differs from Fv1-mediated restriction in that TRIM5␣-mediated restriction is manifested earlier in the infectious pathway, b...

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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).…”

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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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The human and African green monkey TRIM5α genes encode Ref1 and Lv1 retroviral restriction factor activities

Cited by 321 publications

References 44 publications

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

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

TRIM5α Cytoplasmic Bodies Are Highly Dynamic Structures

Cellular Restriction of Retrovirus Particle-Mediated mRNA Transfer

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