133 results found
Cottee MA, Beckwith SL, Letham SC, et al., 2021, Structure of a Ty1 restriction factor reveals the molecular basis of transposition copy number control, NATURE COMMUNICATIONS, Vol: 12
Young GR, Ferron AKW, Panova V, et al., 2021, Gv1, a Zinc Finger Gene Controlling Endogenous MLV Expression, MOLECULAR BIOLOGY AND EVOLUTION, Vol: 38, Pages: 2468-2474, ISSN: 0737-4038
Yap MW, Young GR, Varnaite R, et al., 2020, Duplication and divergence of the retrovirus restriction gene Fv1 in Mus caroli allows protection from multiple retroviruses, PLOS GENETICS, Vol: 16, ISSN: 1553-7404
Panova V, Attig J, Young GR, et al., 2020, Antibody-induced internalisation of retroviral envelope glycoproteins is a signal initiation event, PLOS PATHOGENS, Vol: 16, ISSN: 1553-7366
Cottee MA, Letham SC, Young GR, et al., 2020, Structure of Drosophila melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag, Science Advances, Vol: 6, ISSN: 2375-2548
The tetrapod neuronal protein ARC and its Drosophila melanogaster homolog, dARC1, have important but differing roles in neuronal development. Both are thought to originate through exaptation of ancient Ty3/Gypsy retrotransposon Gag, with their novel function relying on an original capacity for self-assembly and encapsidation of nucleic acids. Here, we present the crystal structure of dARC1 CA and examine the relationship between dARC1, mammalian ARC, and the CA protein of circulating retroviruses. We show that while the overall architecture is highly related to that of orthoretroviral and spumaretroviral CA, there are substantial deviations in both amino- and carboxyl-terminal domains, potentially affecting recruitment of partner proteins and particle assembly. The degree of sequence and structural divergence suggests that Ty3/Gypsy Gag has been exapted on two separate occasions and that, although mammalian ARC and dARC1 share functional similarity, the structures have undergone different adaptations after appropriation into the tetrapod and insect genomes.
Acton O, Grant T, Nicastro G, et al., 2019, Structural basis for Fullerene geometry in a human endogenous retrovirus capsid, NATURE COMMUNICATIONS, Vol: 10, ISSN: 2041-1723
Yap MW, Young GR, Varnaite R, et al., 2019, Duplication and divergence of the retrovirus restriction geneFv1inMus carolimice allows protection from multiple retroviruses
<jats:title>Abstract</jats:title><jats:p>Viruses and their hosts are locked in an evolutionary race where resistance to infection is acquired by the hosts while viruses develop strategies to circumvent these host defenses. Forming one arm of the host defense armory are cell autonomous restriction factors like Fv1. Originally described as protecting laboratory mice from infection by murine leukemia virus (MLV), Fv1s from some wild mice have also been found to restrict non-MLV retroviruses, suggesting an important role in the protection against viruses in nature. To begin to understand how restriction factors evolve, we surveyed the<jats:italic>Fv1</jats:italic>genes of wild mice trapped in Thailand and characterized their restriction activities against a panel of retroviruses. An extra copy of the<jats:italic>Fv1</jats:italic>gene, named Fv7, was found on chromosome 6 of three closely related Asian species of mice (<jats:italic>Mus caroli</jats:italic>,<jats:italic>M. cervicolor</jats:italic>and<jats:italic>M. cookii</jats:italic>). The presence of flanking repeats suggested it arose by LINE-mediated retrotransposition. A high degree of natural variation was observed in both<jats:italic>Fv1</jats:italic>and<jats:italic>Fv7</jats:italic>, including numerous single nucleotide polymorphisms resulting in altered amino acids, as well as insertions and deletions that changed the length of the reading frames. These genes exhibited a range of restriction phenotypes with activities directed against feline foamy virus (FFV), equine infectious anemia virus (EIAV) and MLV. It seems likely, at least in the case of<jats:italic>M. caroli</jats:italic>, that the observed gene duplication confers protection against multiple viruses not possible with a single restriction factor. We suggest that EIAV-, FFV- and MLV-like viruses are endemic within these populations, driving
Attig J, Young GR, Hosie L, et al., 2019, LTR retroelement expansion of the human cancer transcriptome and immunopeptidome revealed by de novo transcript assembly, Genome Research, Vol: 29, Pages: 1578-1590, ISSN: 1054-9803
Dysregulated endogenous retroelements (EREs) are increasingly implicated in the initiation, progression, and immune surveillance of human cancer. However, incomplete knowledge of ERE activity limits mechanistic studies. By using pan-cancer de novo transcript assembly, we uncover the extent and complexity of ERE transcription. The current assembly doubled the number of previously annotated transcripts overlapping with long-terminal repeat (LTR) elements, several thousand of which were expressed specifically in one or a few related cancer types. Exemplified in melanoma, LTR-overlapping transcripts were highly predictable, disease prognostic, and closely linked with molecularly defined subtypes. They further showed the potential to affect disease-relevant genes, as well as produce novel cancer-specific antigenic peptides. This extended view of LTR elements provides the framework for functional validation of affected genes and targets for cancer immunotherapy.
Monit C, Morris ER, Ruis C, et al., 2019, Positive selection in dNTPase SAMHD1 throughout mammalian evolution, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 116, Pages: 18647-18654, ISSN: 0027-8424
Cottee MA, Letham SC, Young GR, et al., 2019, Structure of D. melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag
<jats:title>ABSTRACT</jats:title><jats:p>The tetrapod neuronal protein ARC and its <jats:italic>D. melanogaster</jats:italic> homologue, dARC1, have important but differing roles in neuronal development. Both are thought to originate through exaptation of ancient Ty3/Gypsy retrotransposon Gag genes, with their novel function relying on an original capacity for self-assembly and encapsidation of nucleic acids. Here, we present the crystal structure of dARC1 CA and examine the relationship between dARC1, mammalian ARC and the CA protein of circulating retroviruses. We show that whilst the overall architecture is highly related to that of orthoretroviral and spumaretroviral CA, there are significant deviations in both N- and C-terminal domains, potentially affecting recruitment of partner proteins and particle assembly. The degree of sequence and structural divergence suggests that Ty3/Gypsy Gag has been exapted on two separate occasions and that, although mammalian ARC and dARC1 share functional similarity, the structures have undergone different adaptations after appropriation into the tetrapod and insect genomes.</jats:p>
Keown JR, Black MM, Ferron A, et al., 2018, A helical LC3-interacting region mediates the interaction between the retroviral restriction factor Trim5 and mammalian autophagy-related ATG8 proteins, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 293, Pages: 18378-18386
Ottina E, Levy P, Eksmond U, et al., 2018, Restoration of Endogenous Retrovirus Infectivity Impacts Mouse Cancer Models, CANCER IMMUNOLOGY RESEARCH, Vol: 6, Pages: 1292-1300, ISSN: 2326-6066
Young GR, Yap MW, Michaux JR, et al., 2018, Evolutionary journey of the retroviral restriction gene Fv1, Proceedings of the National Academy of Sciences of the United States of America, Vol: 115, Pages: 10130-10135, ISSN: 0027-8424
Both exogenous and endogenous retroviruses have long been studied in mice, and some of the earliest mouse studies focused on the heritability of genetic factors influencing permissivity and resistance to infection. The prototypic retroviral restriction factor, Fv1, is now understood to exhibit a degree of control across multiple retroviral genera and is highly diverse within Mus. To better understand the age and evolutionary history of Fv1, a comprehensive survey of the Muroidea was conducted, allowing the progenitor integration to be dated to ∼45 million years. Intact coding potential is visible beyond Mus, and sequence analysis reveals strong signatures of positive selection also within field mice, Apodemus. Fv1’s survival for such a period implies a recurring and shifting retroviral burden imparting the necessary selective pressures—an influence likely also common to analogous factors. Regions of Fv1 adapt cooperatively, highlighting its preference for repeated structures and suggesting that this functionally constrained aspect of the retroviral capsid lattice presents a common target in the evolution of intrinsic immunity. restriction factorevolutionhost–virus interactions
Krupovic M, Blomberg J, Coffin JM, et al., 2018, Ortervirales: New Virus Order Unifying Five Families of Reverse-Transcribing Viruses, JOURNAL OF VIROLOGY, Vol: 92, ISSN: 0022-538X
Attig J, Young GR, Stoye JP, et al., 2017, Physiological and pathological transcriptional activation of endogenous retroelements assessed by RNA-sequencing of B lymphocytes, Frontiers in Microbiology, Vol: 8, ISSN: 1664-302X
In addition to evolutionarily-accrued sequence mutation or deletion, endogenous retroelements (EREs) in eukaryotic genomes are subject to epigenetic silencing, preventing or reducing their transcription, particularly in the germplasm. Nevertheless, transcriptional activation of EREs, including endogenous retroviruses (ERVs) and long interspersed nuclear elements (LINEs), is observed in somatic cells, variably upon cellular differentiation and frequently upon cellular transformation. ERE transcription is modulated during physiological and pathological immune cell activation, as well as in immune cell cancers. However, our understanding of the potential consequences of such modulation remains incomplete, partly due to the relative scarcity of information regarding genome-wide ERE transcriptional patterns in immune cells. Here, we describe a methodology that allows probing RNA-sequencing (RNA-seq) data for genome-wide expression of EREs in murine and human cells. Our analysis of B cells reveals that their transcriptional response during immune activation is dominated by induction of gene transcription, and that EREs respond to a much lesser extent. The transcriptional activity of the majority of EREs is either unaffected or reduced by B cell activation both in mice and humans, albeit LINEs appear considerably more responsive in the latter host. Nevertheless, a small number of highly distinct ERVs are strongly and consistently induced during B cell activation. Importantly, this pattern contrasts starkly with B cell transformation, which exhibits widespread induction of EREs, including ERVs that minimally overlap with those responsive to immune stimulation. The distinctive patterns of ERE induction suggest different underlying mechanisms and will help separate physiological from pathological expression.
Eksmond U, Jenkins B, Merkenschlager J, et al., 2017, Mutation of the putative immunosuppressive domain of the retroviral envelope glycoprotein compromises infectivity, Journal of Virology, Vol: 91, ISSN: 1098-5514
The envelope glycoprotein of diverse endogenous and exogenous retroviruses is considered inherently immunosuppressive. Extensive work mapped the immunosuppressive activity to a highly conserved domain, termed the immunosuppressive domain (ISD), in the transmembrane (TM) subunit of the envelope glycoprotein and identified two naturally polymorphic key residues that afford immunosuppressive activity to distinct envelope glycoproteins. Concurrent mutation of these two key residues (E14R and A20F) in the envelope glycoprotein of the Friend murine leukemia virus (F-MLV) ISD has been reported to abolish its immunosuppressive activity, without affecting its fusogenicity, and to weaken the ability of the virus to replicate specifically in immunocompetent hosts. Here, we show that mutation of these key residues did, in fact, result in a substantial loss of F-MLV infectivity, independently of host immunity, challenging whether associations exist between the two. Notably, a loss of infectivity incurred by the F-MLV mutant with the E14R and A20F double ISD mutation was conditional on expression of the ecotropic envelope receptor murine cationic amino acid transporter-1 (mCAT1) in the virus-producing cell. Indeed, the F-MLV mutant retained infectivity when it was produced by human cells, which naturally lack mCAT1 expression, but not by murine cells. Furthermore, mCAT1 overexpression in human cells impaired the infectivity of both the F-MLV double mutant and the wild-type F-MLV strain, suggesting a finely tuned relationship between the levels of mCAT1 in the producer cell and the infectivity of the virions produced. An adverse effect on this relationship, rather than disruption of the putative ISD, is therefore more likely to explain the loss of F-MLV infectivity incurred by mutations in key ISD residues E14 and A20.
Kassiotis G, Stoye JP, 2017, Making a virtue of necessity: the pleiotropic role of human endogenous retroviruses in cancer, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 372, ISSN: 0962-8436
Like all other mammals, humans harbour an astonishing number of endogenous retroviruses (ERVs), as well as other retroelements, embedded in their genome. These remnants of ancestral germline infection with distinct exogenous retroviruses display various degrees of open reading frame integrity and replication capability. Modern day exogenous retroviruses, as well as the infectious predecessors of ERVs, are demonstrably oncogenic. Further, replication-competent ERVs continue to cause cancers in many other species of mammal. Moreover, human cancers are characterized by transcriptional activation of human endogenous retroviruses (HERVs). These observations conspire to incriminate HERVs as causative agents of human cancer. However, exhaustive investigation of cancer genomes suggests that HERVs have entirely lost the ability for re-infection and thus the potential for insertional mutagenic activity. Although there may be non-insertional mechanisms by which HERVs contribute to cancer development, recent evidence also uncovers potent anti-tumour activities exerted by HERV replication intermediates or protein products. On balance, it appears that HERVs, despite their oncogenic past, now represent potential targets for immune-mediated anti-tumour mechanisms.
Taylor WR, Stoye JP, Taylor IA, 2017, A comparative analysis of the foamy and ortho virus capsid structures reveals an ancient domain duplication, BMC STRUCTURAL BIOLOGY, Vol: 17, ISSN: 1472-6807
Ordonez P, Kunzelmann S, Groom HCT, et al., 2017, SAMHD1 enhances nucleoside-analogue efficacy against HIV-1 in myeloid cells, Scientific Reports, Vol: 7, ISSN: 2045-2322
SAMHD1 is an intracellular enzyme that specifically degrades deoxynucleoside triphosphates intocomponent nucleoside and inorganic triphosphate. In myeloid-derived dendritic cells and macrophagesas well as resting T-cells, SAMHD1 blocks HIV-1 infection through this dNTP triphosphohydrolaseactivity by reducing the cellular dNTP pool to a level that cannot support productive reversetranscription. We now show that, in addition to this direct effect on virus replication, manipulatingcellular SAMHD1 activity can significantly enhance or decrease the anti-HIV-1 efficacy of nucleotideanalogue reverse transcription inhibitors presumably as a result of modulating dNTP pools thatcompete for recruitment by viral polymerases. Further, a variety of other nucleotide-based analogues,not normally considered antiretrovirals, such as the anti-herpes drugs Aciclovir and Ganciclovir and theanti-cancer drug Clofarabine are now revealed as potent anti-HIV-1 agents, under conditions of lowdNTPs. This in turn suggests novel uses for nucleotide analogues to inhibit HIV-1 in differentiated cellslow in dNTPs.
Buseyne F, Gessain A, Soares MA, et al., 2016, Eleventh International Foamy Virus ConferenceMeeting Report, VIRUSES-BASEL, Vol: 8, ISSN: 1999-4915
Ball NJ, Nicastro G, Dutta M, et al., 2016, Structure of a spumaretrovirus gag central domain reveals an ancient retroviral capsid, PLoS Pathogens, Vol: 12, ISSN: 1553-7366
The Spumaretrovirinae, or foamy viruses (FVs) are complex retroviruses that infect many species of monkey and ape. Despite little sequence homology, FV and orthoretroviral Gag proteins perform equivalent functions, including genome packaging, virion assembly, trafficking and membrane targeting. However, there is a paucity of structural information for FVs and it is unclear how disparate FV and orthoretroviral Gag molecules share the same function. To probe the functional overlap of FV and orthoretroviral Gag we have determined the structure of a central region of Gag from the Prototype FV (PFV). The structure comprises two all α-helical domains NtDCEN and CtDCEN that although they have no sequence similarity, we show they share the same core fold as the N- (NtDCA) and C-terminal domains (CtDCA) of archetypal orthoretroviral capsid protein (CA). Moreover, structural comparisons with orthoretroviral CA align PFV NtDCEN and CtDCEN with NtDCA and CtDCA respectively. Further in vitro and functional virological assays reveal that residues making inter-domain NtDCEN—CtDCEN interactions are required for PFV capsid assembly and that intact capsid is required for PFV reverse transcription. These data provide the first information that relates the Gag proteins of Spuma and Orthoretrovirinae and suggests a common ancestor for both lineages containing an ancient CA fold.
Mavrommatis B, Baudino L, Levy P, et al., 2016, Dichotomy between T Cell and B Cell Tolerance to Neonatal Retroviral Infection Permits T Cell Therapy, JOURNAL OF IMMUNOLOGY, Vol: 197, Pages: 3628-3638, ISSN: 0022-1767
Elucidation of the immune requirements for control or elimination of retroviral infection remains an important aim. We studied the induction of adaptive immunity to neonatal infection with a murine retrovirus, under conditions leading to immunological tolerance. We found that the absence of either maternal or offspring adaptive immunity permitted efficient vertical transmission of the retrovirus. Maternal immunodeficiency allowed the retrovirus to induce central Th cell tolerance in the infected offspring. In turn, this compromised the offspring’s ability to mount a protective Th cell–dependent B cell response. However, in contrast to T cells, offspring B cells were not centrally tolerized and retained their ability to respond to the infection when provided with T cell help. Thus, escape of retrovirus-specific B cells from deletional tolerance offers the opportunity to induce protective retroviral immunity by restoration of retrovirus-specific T cell help, suggesting similar T cell immunotherapies for persistent viral infections.
Li W, Yap MW, Voss V, et al., 2016, Expression levels of Fv1: effects on retroviral restriction specificities, RETROVIROLOGY, Vol: 13, ISSN: 1742-4690
BackgroundThe mouse protein Fv1 is a factor that can confer resistance to retroviral infection. The two major Fv1 alleles from laboratory mice, Fv1 n and Fv1 b , restrict infection by different murine leukaemia viruses (MLVs). Fv1n restricts B-tropic MLV, but not N-tropic MLV or NB-tropic MLV. In cells expressing Fv1b at natural levels, only N-MLV is restricted, however restriction of NB-MLV and partial restriction of B-MLV were observed when recombinant Fv1b was expressed from an MLV promoter in Fv1 null Mus dunni tail fibroblast cells. To investigate the relationship between expression level and restriction specificity we have developed new retroviral delivery vectors which allow inducible expression of Fv1, and yet allow sufficient production of fluorescent reporter proteins for analysis in our FACS-based restriction assay.ResultsWe demonstrated that at concentrations close to the endogenous expression level, Fv1b specifically restricts only N-MLV, but restriction of NB-MLV, and to a lesser extent B-MLV, could be gained by increasing the protein level of Fv1b. By contrast, we found that even when Fv1n is expressed at very high levels, no significant inhibition of N-MLV or NB-MLV could be observed. Study of Fv1 mutants using this assay led to the identification of determinants for N/B tropism at an expression level close to that of endogenous Fv1n and Fv1b. We also compared the recently described restriction activities of wild mice Fv1 proteins directed against non-MLV retroviruses when expressed at different levels. Fv1 from M. spretus restricted N-MLV, B-MLV and equine infectious anaemia virus equally even at low concentrations, while Fv1 from M. macedonicus showed even stronger restriction against equine infectious anaemia virus than to N-MLV. Restriction of feline foamy virus by Fv1 of M. caroli occurred at levels equivalent to MLV restriction.ConclusionsOur data indicate that for some but not all Fv1 proteins, gain of restriction activities could be achieved
Kassiotis G, Stoye JP, 2016, Immune responses to endogenous retroelements: taking the bad with the good, NATURE REVIEWS IMMUNOLOGY, Vol: 16, Pages: 207-219, ISSN: 1474-1733
Arnold LH, Groom HCT, Kunzelmann S, et al., 2015, Phospho-dependent Regulation of SAMHD1 Oligomerisation Couples Catalysis and Restriction, PLOS PATHOGENS, Vol: 11, ISSN: 1553-7366
Schwefel D, Boucherit VC, Christodoulou E, et al., 2015, Molecular determinants for recognition of divergent SAMHD1 proteins by the lentiviral accessory protein Vpx, Cell Host and Microbe, Vol: 17, Pages: 489-499, ISSN: 1931-3128
The SAMHD1 triphosphohydrolase inhibits HIV-1 infection of myeloid and resting T cells by depleting dNTPs. To overcome SAMHD1, HIV-2 and some SIVs encode either of two lineages of the accessory protein Vpx that bind the SAMHD1 N or C terminus and redirect the host cullin-4 ubiquitin ligase to target SAMHD1 for proteasomal degradation. We present the ternary complex of Vpx from SIV that infects mandrills (SIVmnd-2) with the cullin-4 substrate receptor, DCAF1, and N-terminal and SAM domains from mandrill SAMHD1. The structure reveals details of Vpx lineage-specific targeting of SAMHD1 N-terminal “degron” sequences. Comparison with Vpx from SIV that infects sooty mangabeys (SIVsmm) complexed with SAMHD1-DCAF1 identifies molecular determinants directing Vpx lineages to N- or C-terminal SAMHD1 sequences. Inspection of the Vpx-DCAF1 interface also reveals conservation of Vpx with the evolutionally related HIV-1/SIV accessory protein Vpr. These data suggest a unified model for how Vpx and Vpr exploit DCAF1 to promote viral replication.
Mager DL, Stoye JP, 2015, Mammalian Endogenous Retroviruses, MICROBIOLOGY SPECTRUM, Vol: 3, ISSN: 2165-0497
Goldstone DC, Walker PA, Calder LJ, et al., 2014, Structural studies of postentry restriction factors reveal antiparallel dimers that enable avid binding to the HIV-1 capsid lattice, Proceedings of the National Academy of Sciences of the United States of America, Vol: 111, Pages: 9609-9614, ISSN: 0027-8424
Restriction factors (RFs) form important components of host defenses to retroviral infection. The Fv1, Trim5α, and TrimCyp RFs contain N-terminal dimerization and C-terminal specificity domains that target assembled retroviral capsid (CA) proteins enclosing the viral core. However, the molecular detail of the interaction between RFs and their CA targets is unknown. Therefore, we have determined the crystal structure of the B-box and coiled-coil (BCC) region from Trim5α and used small-angle X-ray scattering to examine the solution structure of Trim5α BCC, the dimerization domain of Fv1 (Fv1Ntd), and the hybrid restriction factor Fv1Cyp comprising Fv1NtD fused to the HIV-1 binding protein Cyclophilin A (CypA). These data reveal that coiled-coil regions of Fv1 and Trim5α form extended antiparallel dimers. In Fv1Cyp, two CypA moieties are located at opposing ends, creating a molecule with a dumbbell appearance. In Trim5α, the B-boxes are located at either end of the coiled-coil, held in place by interactions with a helical motif from the L2 region of the opposing monomer. A comparative analysis of Fv1Cyp and CypA binding to a preformed HIV-1 CA lattice reveals how RF dimerization enhances the affinity of interaction through avidity effects. We conclude that the antiparallel organization of the NtD regions of Fv1 and Trim5α dimers correctly positions C-terminal specificity and N-terminal effector domains and facilitates stable binding to adjacent CA hexamers in viral cores.
Yap MW, Colbeck E, Ellis SA, et al., 2014, Evolution of the retroviral restriction gene Fv1: inhibition of non-MLV retroviruses, PLoS Pathogens, Vol: 10, Pages: 1-14, ISSN: 1553-7366
Fv1 is the prototypic restriction factor that protects against infection by the murine leukemia virus (MLV). It was first identified in cells that were derived from laboratory mice and was found to be homologous to the gag gene of an endogenous retrovirus (ERV). To understand the evolution of the host restriction gene from its retroviral origins, Fv1s from wild mice were isolated and characterized. Most of these possess intact open reading frames but not all restricted N-, B-, NR-or NB-tropic MLVs, suggesting that other viruses could have played a role in the selection of the gene. The Fv1s from Mus spretus and Mus caroli were found to restrict equine infectious anemia virus (EIAV) and feline foamy virus (FFV) respectively, indicating that Fv1 could have a broader target range than previously thought, including activity against lentiviruses and spumaviruses. Analyses of the Fv1 sequences revealed a number of residues in the C-terminal region that had evolved under positive selection. Four of these selected residues were found to be involved in the novel restriction by mapping studies. These results strengthen the similarities between the two capsid binding restriction factors, Fv1 and TRIM5α, which support the hypothesis that Fv1 defended mice against waves of retroviral infection possibly including non-MLVs as well as MLVs.
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