Publications (6)34.65 Total impact
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Article: Porcine endogenous retroviruses PERV A and A/C recombinant are insensitive to a range of divergent mammalian TRIM5alpha proteins including human TRIM5alpha.
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ABSTRACT: The potential risk of cross-species transmission of porcine endogenous retroviruses (PERV) to humans has slowed the development of xenotransplantation, using pigs as organ donors. Here, we show that PERVs are insensitive to restriction by divergent TRIM5alpha molecules despite the fact that they strongly restrict a variety of divergent lentiviruses. We also show that the human PERV A/C recombinant clone 14/220 reverse transcribes with increased efficiency in human cells, leading to significantly higher infectivity. We conclude that xenotransplantation studies should consider the danger of highly infectious TRIM5alpha-insensitive human-tropic PERV recombinants.Journal of General Virology 04/2009; 90(Pt 3):702-9. · 3.36 Impact Factor -
Article: Rhesus macaque TRIM5 alleles have divergent antiretroviral specificities.
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ABSTRACT: TRIM5alpha is a potent barrier to cross-species retroviral transmission, and TRIM5alphas from different species have divergent antiretroviral specificities. Multiple TRIM5 alleles circulate within rhesus macaque populations. Here we show that they too have different antiretroviral specificities, highlighting how TRIM5 genotypes contribute to protection in an individual or a population.Journal of Virology 08/2008; 82(14):7243-7. · 5.40 Impact Factor -
Article: Independent evolution of an antiviral TRIMCyp in rhesus macaques.
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ABSTRACT: The antiretroviral restriction factor TRIM5 has recently emerged as an important mediator of innate immunity and species-specific inhibition of retroviral replication in mammals. Selection pressure from pathogenic infection has driven rapid evolution of TRIM5 genes, leading to the antiviral specificities we see today. Remarkably, the New World owl monkey (Aotus trivirgatus) encodes a TRIM5 protein in which the antiviral determinants in the B30.2 domain have been replaced by cyclophilin A (CypA) encoded by a retrotransposed cDNA. The owl monkey TRIMCyp protein restricts infection by a subset of lentiviruses that recruit CypA to their capsids, including HIV-1 and feline immunodeficiency virus. Here, we show that the Old World monkey, rhesus macaque (Macaca mulatta), also encodes a TRIMCyp protein that has arisen independently from that in owl monkeys. The rhesus TRIMCyp is encoded by a single, but common, allele (Mamu7) of the rhesus TRIM5 gene, among at least six further alleles that encode full-length TRIM5 proteins with no homology to CypA. The antiviral specificity of the rhesus TRIMCyp is distinct, restricting infection of HIV-2 and feline immunodeficiency virus but not HIV-1. Restriction by rhesus TRIMCyp is before reverse transcription and inhibited by blocking CypA binding, with cyclosporine A, or by mutation of the capsid CypA binding site. These observations suggest a mechanism of restriction that is conserved between TRIMCyp proteins. The lack of activity against HIV-1 suggests that Mamu7 homozygous animals will be null for TRIM5-mediated restriction of HIV-1 and could contribute to improved animal models for HIV/AIDS.Proceedings of the National Academy of Sciences 04/2008; 105(9):3557-62. · 9.68 Impact Factor -
Article: X box binding protein XBP-1s transactivates the Kaposi's sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency.
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ABSTRACT: Reactivation of lytic replication from viral latency is a defining property of all herpesviruses. Despite this, the authentic physiological cues for the latent-lytic switch are unclear. Such cues should ensure that viral lytic replication occurs under physiological conditions, predominantly in sites which facilitate transmission to permissive uninfected cells and new susceptible hosts. Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with the B-cell neoplasm primary effusion lymphoma (PEL), in which the virus remains latent. We have previously shown that PEL cells have the gene expression profile and immunophenotype of cycling preplasma cells (plasmablasts). Here, we show that the highly active spliced isoform of plasma cell transcription factor X box binding protein 1 (XBP-1s) is a lytic switch for KSHV. XBP-1s is normally absent in PEL, but the induction of endoplasmic reticulum stress leads to XBP-1s generation, plasma cell-like differentiation, and lytic reactivation of KSHV. XBP-1s binds to and activates the KSHV immediate-early gene ORF50 and synergizes with the ORF50 gene product RTA to induce a full lytic cycle. These data suggest that KSHV remains latent until B-cell terminal differentiation into plasma cells, the transcriptional environment of which provides the physiological "lytic switch" through XBP-1s. This links B-cell terminal differentiation to KSHV lytic reactivation.Journal of Virology 01/2008; 81(24):13578-86. · 5.40 Impact Factor -
Article: Fusion of cyclophilin A to Fv1 enables cyclosporine-sensitive restriction of human and feline immunodeficiency viruses.
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ABSTRACT: TRIM5alpha is a potent intracellular antiviral restriction factor governing species-specific retroviral replication. In the New World species owl monkey the coding region for the viral binding B30.2 domain of TRIM5alpha has been replaced by a cyclophilin A (CypA) pseudogene by retrotransposition. The resultant TRIM5-CypA fusion protein restricts human immunodeficiency virus type 1 (HIV-1), as well as feline immunodeficiency virus (FIV), by recruitment of the CypA domain to the incoming viral capsids. Infectivity is rescued by agents such as cyclosporine that disrupt CypA binding to its substrates. Mice encode an antiviral restriction factor called Fv1 (for Friend virus susceptibility gene 1), which is active against murine leukemia virus and related to endogenous gag sequences. Here we show that fusing CypA to Fv1 generates a restriction factor with the antiviral specificity of TRIMCyp but the antiviral properties of Fv1. Like TRIMCyp, Fv1-Cyp restricts HIV-1 and FIV and is sensitive to inhibition by cyclosporine. TRIM5alpha is known to have a short half-life and block infectivity before viral reverse transcription. We show that Fv1-Cyp has a long half-life and blocks after reverse transcription, suggesting that its longer half-life gives the restricted virus the opportunity to synthesize DNA, leading to a later block to infection. This notion is supported by the observation that infectivity of Fv1-Cyp restricted virus can be rescued by cyclosporine for several hours after infection, whereas virus restricted by TRIMCyp is terminally restricted after around 40 min. Intriguingly, the Fv1-Cyp-restricted HIV-1 generates closed circular viral DNA, suggesting that the restricted virus complex enters the nucleus.Journal of Virology 10/2007; 81(18):10055-63. · 5.40 Impact Factor -
Article: Isolation of an active Lv1 gene from cattle indicates that tripartite motif protein-mediated innate immunity to retroviral infection is widespread among mammals.
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ABSTRACT: Lv1/TRIM5alpha (tripartite motif 5alpha) has recently emerged as an important factor influencing species-specific permissivity to retroviral infection in a range of primates, including humans. Old World monkey TRIM5alpha blocks human immunodeficiency virus type 1 (HIV-1) infectivity, and the human and New World monkey TRIM5alpha proteins are inactive against HIV-1 but active against divergent murine (N-tropic murine leukemia virus [MLV-N]) and simian (simian immunodeficiency virus from rhesus macaque [SIVmac]) retroviruses, respectively. Here we demonstrate antiviral activity of the first nonprimate TRIM protein, from cattle, active against divergent retroviruses, including HIV-1. The number of closely related human TRIM sequences makes assignment of the bovine sequence as a TRIM5alpha ortholog uncertain, and we therefore refer to it as bovine Lv1. Bovine Lv1 is closely related to primate TRIM5alpha proteins in the N-terminal RING and B-box 2 domains but significantly less homologous in the C-terminal B30.2 domain, particularly in the region shown to influence antiviral specificity. Intriguingly, some viruses restricted by bovine Lv1, including HIV-1 and MLV-N, are unable to synthesize viral DNA by reverse transcription, whereas restricted HIV-2 makes normal amounts of DNA. The data support the conclusion that TRIM protein-mediated restriction of retroviral infection is a more common attribute of mammals than previously appreciated.Journal of Virology 09/2006; 80(15):7332-8. · 5.40 Impact Factor
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Institutions
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2006–2009
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University College London
- Division of Infection and Immunity
London, ENG, United Kingdom
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