References of "Gillet, Nicolas"
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See detailRecent advances in BLV research
Barez, Pierre-Yves ULg; De Brogniez, Alix ULg; Carpentier, Alexandre ULg et al

in Viruses (2015), 7(11), 6080-6088

Different animal models have been proposed to investigate the mechanisms of HTLV-induced pathogenesis: rats, transgenic and NOD-SCID/γcnull (NOG) mice, rabbits, squirrel monkeys, baboons and macaques ... [more ▼]

Different animal models have been proposed to investigate the mechanisms of HTLV-induced pathogenesis: rats, transgenic and NOD-SCID/γcnull (NOG) mice, rabbits, squirrel monkeys, baboons and macaques. These systems indeed provide useful information but have intrinsic limitations such as lack of disease relevance, species specificity or inadequate immune response. Another strategy based on a comparative virology approach is to characterize a related pathogen and to speculate on possible shared mechanisms. In this perspective, bovine leukemia virus (BLV), another member of the deltaretrovirus genus, is evolutionary related to HTLV-1. BLV induces lymphoproliferative disorders in ruminants providing useful information on the mechanisms of viral persistence, genetic determinants of pathogenesis and potential novel therapies. [less ▲]

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See detailModes of Human T Cell Leukemia Virus Type 1 Transmission, Replication and Persistence
Carpentier, Alexandre ULg; Barez, Pierre-Yves ULg; Hamaïdia, Malik ULg et al

in Viruses (2015), 7

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes cancer (Adult T cell Leukemia, ATL) and a spectrum of inflammatory diseases (mainly HTLV-associated myelopathy—tropical spastic ... [more ▼]

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes cancer (Adult T cell Leukemia, ATL) and a spectrum of inflammatory diseases (mainly HTLV-associated myelopathy—tropical spastic paraparesis, HAM/TSP). Since virions are particularly unstable, HTLV-1 transmission primarily occurs by transfer of a cell carrying an integrated provirus. After transcription, the viral genomic RNA undergoes reverse transcription and integration into the chromosomal DNA of a cell from the newly infected host. The virus then replicates by either one of two modes: (i) an infectious cycle by virus budding and infection of new targets and (ii) mitotic division of cells harboring an integrated provirus. HTLV-1 replication initiates a series of mechanisms in the host including antiviral immunity and checkpoint control of cell proliferation. HTLV-1 has elaborated strategies to counteract these defense mechanisms allowing continuous persistence in humans. [less ▲]

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See detailAPOBEC3 Interference during Replication of Viral Genomes
Willems, Luc ULg; Gillet, Nicolas ULg

in Viruses (2015)

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See detailRisk of emergence of a hyperpathogenic bovine leukemia virus by mutation of a single envelope N-linked glycosylation site
De Brogniez, Alix ULg; Bouzar, Amel-Baya; Jacques, Jean-Rock ULg et al

Poster (2015, February 11)

- Introduction : Pathogens have co-evolved with their host to ensure efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is ... [more ▼]

- Introduction : Pathogens have co-evolved with their host to ensure efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by the bovine leukemia virus (BLV) system in which lymphoproliferative disorders develop in ruminants after latency periods of several years. Infection of sheep and cattle with BLV is a model system for the related human T-lymphotropic virus type 1 (HTLV-1) responsible for Adult T-cell Leukemia (ATL). - Aims : The goal of this work is to investigate the role of N-glycans of the viral envelope protein during viral replication and pathogenesis. - Methods and results : Using glycosylation inhibitors and lectins, we showed that N-glycosylation is involved in viral infection (i.e. cell-to-cell fusion). Using reverse genetics of an infectious molecular provirus, we next demonstrated that a particular N-linked envelope glycosylation site (N230) limits viral replication and pathogenicity in vitro and in vivo. We have thus generated a viral mutant that is more pathogenic than the wild type strain. - Conclusions : To our knowledge, this is the first time that a hyperpathogenic BLV has been identified. This unexpected observation has important consequences in terms of disease control and managing. Indeed, during evolution, pathogens and their hosts should achieve an equilibrium allowing the coexistence of the two species. Occurrence of this particular mutation may thus represent a potential threat associated with emergence of hyperpathogenic BLV strains and possibly of new variants of the related HTLV-1. [less ▲]

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See detailMutation of a Single Envelope N-linked Glycosylation Site Enhances the Pathogenicity of Bovine Leukemia Virus
De Brogniez, Alix ULg; Bouzar, Amel-Baya; Jacques, Jean-Rock ULg et al

in Journal of Virology (2015), 89(17),

Viruses have co-evolved with their host to ensure efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by the ... [more ▼]

Viruses have co-evolved with their host to ensure efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by the bovine leukemia virus (BLV) system in which lymphoproliferative disorders develop in ruminants after latency periods of several years. In principle, the equilibrium reached between the virus and its host could be disrupted by emergence of more pathogenic strains. Intriguingly but fortunately, such a hyperpathogenic BLV strain was never observed in the field nor designed in vitro. In this study, we aimed at understanding the role of envelope N-linked glycosylation with the hypothesis that this posttranslational modification could either favor BLV infection by allowing viral entry or allow immune escape by using glycans as a shield. Using reverse genetics of an infectious molecular provirus, we have identified a N-linked envelope glycosylation site (N230) that limits viral replication and pathogenicity. Indeed, mutation N230E unexpectedly leads to enhanced fusogenicity and protein stability. Occurrence of this mutation may thus represent a potential threat associated with emergence of hyperpathogenic BLV strains and possibly of new variants of the related primate T-lymphotropic viruses. [less ▲]

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See detailRisk of emergence of a hyperpathogenic bovine leukemia virus by mutation of a single envelope N-linked glycosylation site
De Brogniez, Alix ULg; Bouzar, Amel-Baya; Jacques, Jean-Rock ULg et al

Scientific conference (2014, December 08)

Pathogens have co-evolved with their host to allow efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by ... [more ▼]

Pathogens have co-evolved with their host to allow efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by the bovine leukemia virus (BLV) model that induces lymphoproliferative disorders in ruminants only after extended latency periods of several years. In principle, the equilibrium reached between the virus and its host could be disrupted by emergence of more pathogenic strains. Intriguingly, this type of hyperpathogenic BLV strain could never been isolated in vivo nor designed in vitro. Using reverse genetics of an infectious molecular provirus, we have now identified a N-linked envelope glycosylation site that limits viral replication and pathogenicity. Onset of this particular mutation may thus represent a potential threat associated with emergence of hyperpathogenic BLV strains and possibly of new variants of the related primate T-lymphotropic viruses. [less ▲]

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See detailA Single Envelope N-linked Glycosylation Site Defines Hyperpathogenicity of Bovine Leukemia Virus
De Brogniez, Alix ULg; Bouzar, Amel-Baya; Jacques, Jean-Rock ULg et al

Conference (2014, June 05)

Pathogens have co-evolved with their host to allow efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by ... [more ▼]

Pathogens have co-evolved with their host to allow efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by the bovine leukemia virus (BLV) model that induces lymphoproliferative disorders in ruminants only after extended latency periods of several years. In principle, the equilibrium reached between the virus and its host could be disrupted by emergence of more pathogenic strains. Intriguingly, this type of hyperpathogenic BLV strain could never been isolated in vivo nor designed in vitro. Using reverse genetics of an infectious molecular provirus, we have now identified a N-linked envelope glycosylation site that limits viral replication and pathogenicity. Onset of this particular mutation may thus represent a potential threat associated with emergence of hyperpathogenic BLV strains and possibly of new variants of the related primate T-lymphotropic viruses. [less ▲]

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See detailMassive Depletion of Bovine Leukemia Virus Proviral Clones Located in Genomic Transcriptionally Active Sites During Primary Infection
Gillet, Nicolas ULg; geronimo, gutierrez; rodriguez, sabrina et al

Poster (2014, April)

Deltaretroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) induce a persistent infection generally asymptomatic but can also lead to leukemia or lymphoma. These ... [more ▼]

Deltaretroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) induce a persistent infection generally asymptomatic but can also lead to leukemia or lymphoma. These viruses replicate by infecting new lymphocytes (i.e. the infectious cycle) or via clonal expansion of the infected cells (mitotic cycle). The relative importance of these two cycles in viral replication varies during infection. The majority of infected clones are created early before the onset of an efficient immune response. Later on, the main replication route is mitotic expansion of pre-existing infected clones. Due to the paucity of available samples and for ethical reasons, only scarce data is available on early infection by HTLV-1. Therefore, we addressed this question in a comparative BLV model. We used high-throughput sequencing to map and quantify the insertion sites of the provirus in order to monitor the clonality of the BLV-infected cells population (i.e. the number of distinct clones and abundance of each clone). We found that BLV propagation shifts from cell neoinfection to clonal proliferation in about 2 months from inoculation. Initially, BLV proviral integration significantly favors transcribed regions of the genome. Negative selection then eliminates 97% of the clones detected at seroconversion and disfavors BLV-infected cells carrying a provirus located close to a promoter or a gene. Nevertheless, among the surviving proviruses, clone abundance positively correlates with proximity of the provirus to a transcribed region. Two opposite forces thus operate during primary infection and dictate the fate of long term clonal composition: (1) initial integration inside genes or promoters and (2) host negative selection disfavoring proviruses located next to transcribed regions. The result of this initial response will contribute to the proviral load set point value as clonal abundance will benefit from carrying a provirus in transcribed regions. [less ▲]

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See detailHyper-replicative bovine leukemia virus by mutation of an envelope N-linked glycosylation site
De Brogniez, Alix ULg; Bouzar, Amel-Baya; Jacques, Jean-Rock ULg et al

in Retrovirology (2014), 11(1), 141

Reverse genetics can be used in the bovine leukemia virus (BLV) system to characterize mechanisms of viral persistence and pathogenesis. The question addressed here pertains to the role of glycans bound ... [more ▼]

Reverse genetics can be used in the bovine leukemia virus (BLV) system to characterize mechanisms of viral persistence and pathogenesis. The question addressed here pertains to the role of glycans bound to the BLV envelope glycoprotein (SU). A commonly accepted hypothesis is that addition of carbohydrates to the SU protein potentially creates a structure called « glycan shield » that confers resistance to the virus against the host immune response. On the other hand, glycosylation can also modulate attachment of the virus to the cell membrane. To unravel the role of SU glycosylation, three complementary strategies were developed: pharmacological inhibition of different glycosylation pathways, interference with glycan attachment and site-directed mutagenesis of N-glycosylation sites in an infectious BLV provirus. The different approaches show that glycosylation is required for cell fusion, as expected. Simultaneous mutation of all 8 potential N-glycosylation sites destroys infectivity. Surprisingly, mutation of the asparagine residue at position 230 creates a virus having an increased capacity to form syncytia in vitro. Compared to wild-type BLV, mutant N230 also replicates at accelerated rates in vivo. Collectively, this data thus illustrates an example of a N-glycosylation site that restricts viral replication, contrasting with the hypothesis supported by glycan shield model. [less ▲]

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See detailVaccination against delta-Retroviruses: The Bovine Leukemia Virus Paradigm.
Gutierrez, Geronimo; Rodriguez, Sabrina M.; De Brogniez, Alix ULg et al

in Viruses (2014), 6(6), 2416-2427

Bovine leukemia virus (BLV) and human T-lymphotropic virus type 1 (HTLV-1) are closely related d-retroviruses that induce hematological diseases. HTLV-1 infects about 15 million people worldwide, mainly ... [more ▼]

Bovine leukemia virus (BLV) and human T-lymphotropic virus type 1 (HTLV-1) are closely related d-retroviruses that induce hematological diseases. HTLV-1 infects about 15 million people worldwide, mainly in subtropical areas. HTLV-1 induces a wide spectrum of diseases (e.g., HTLV-associated myelopathy/tropical spastic paraparesis) and leukemia/lymphoma (adult T-cell leukemia). Bovine leukemia virus is a major pathogen of cattle, causing important economic losses due to a reduction in production, export limitations and lymphoma-associated death. In the absence of satisfactory treatment for these diseases and besides the prevention of transmission, the best option to reduce the prevalence of d-retroviruses is vaccination. Here, we provide an overview of the different vaccination strategies in the BLV model and outline key parameters required for vaccine efficacy. [less ▲]

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See detailQuantification of HTLV-1 Clonality and TCR Diversity.
Laydon, Daniel J.; Melamed, Anat; Sim, Aaron et al

in PLoS computational biology (2014), 10(6), 1003646

Estimation of immunological and microbiological diversity is vital to our understanding of infection and the immune response. For instance, what is the diversity of the T cell repertoire? These questions ... [more ▼]

Estimation of immunological and microbiological diversity is vital to our understanding of infection and the immune response. For instance, what is the diversity of the T cell repertoire? These questions are partially addressed by high-throughput sequencing techniques that enable identification of immunological and microbiological "species" in a sample. Estimators of the number of unseen species are needed to estimate population diversity from sample diversity. Here we test five widely used non-parametric estimators, and develop and validate a novel method, DivE, to estimate species richness and distribution. We used three independent datasets: (i) viral populations from subjects infected with human T-lymphotropic virus type 1; (ii) T cell antigen receptor clonotype repertoires; and (iii) microbial data from infant faecal samples. When applied to datasets with rarefaction curves that did not plateau, existing estimators systematically increased with sample size. In contrast, DivE consistently and accurately estimated diversity for all datasets. We identify conditions that limit the application of DivE. We also show that DivE can be used to accurately estimate the underlying population frequency distribution. We have developed a novel method that is significantly more accurate than commonly used biodiversity estimators in microbiological and immunological populations. [less ▲]

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See detailMassive Depletion of Bovine Leukemia Virus Proviral Clones Located in Genomic Transcriptionally Active Sites During Primary Infection
Gillet, Nicolas ULg; Gutiérrez, Gerónimo; Rodriguez, Sabrina ULg et al

in PLoS Pathogens (2013), 9(10),

Deltaretroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) induce a persistent infection generally asymptomatic but can also lead to leukemia or lymphoma. These ... [more ▼]

Deltaretroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) induce a persistent infection generally asymptomatic but can also lead to leukemia or lymphoma. These viruses replicate by infecting new lymphocytes (i.e. the infectious cycle) or via clonal expansion of the infected cells (mitotic cycle). The relative importance of these two cycles in viral replication varies during infection. The majority of infected clones are created early before the onset of an efficient immune response. Later on, the main replication route is mitotic expansion of pre-existing infected clones. Due to the paucity of available samples and for ethical reasons, only scarce data is available on early infection by HTLV-1. Therefore, we addressed this question in a comparative BLV model. We used high-throughput sequencing to map and quantify the insertion sites of the provirus in order to monitor the clonality of the BLV-infected cells population (i.e. the number of distinct clones and abundance of each clone). We found that BLV propagation shifts from cell neoinfection to clonal proliferation in about 2 months from inoculation. Initially, BLV proviral integration significantly favors transcribed regions of the genome. Negative selection then eliminates 97% of the clones detected at seroconversion and disfavors BLV-infected cells carrying a provirus located close to a promoter or a gene. Nevertheless, among the surviving proviruses, clone abundance positively correlates with proximity of the provirus to a transcribed region. Two opposite forces thus operate during primary infection and dictate the fate of long term clonal composition: (1) initial integration inside genes or promoters and (2) host negative selection disfavoring proviruses located next to transcribed regions. The result of this initial response will contribute to the proviral load set point value as clonal abundance will benefit from carrying a provirus in transcribed regions. [less ▲]

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See detailMassive Depletion of Bovine Leukemia Virus Proviral Clones Located in Genomic Transcriptionally Active Sites During Primary Infection
Gillet, Nicolas ULg; Gutiérrez, Gerónimo; Rodriguez, Sabrina et al

Conference (2013, June 29)

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See detailStrongyloidiasis and Infective Dermatitis Alter Human T Lymphotropic Virus-1 Clonality in vivo.
Gillet, Nicolas ULg; Cook, Lucy; Laydon, Daniel J. et al

in PLoS Pathogens (2013), 9(4), 1003263

Human T-lymphotropic Virus-1 (HTLV-1) is a retrovirus that persists lifelong by driving clonal proliferation of infected T-cells. HTLV-1 causes a neuroinflammatory disease and adult T-cell leukemia ... [more ▼]

Human T-lymphotropic Virus-1 (HTLV-1) is a retrovirus that persists lifelong by driving clonal proliferation of infected T-cells. HTLV-1 causes a neuroinflammatory disease and adult T-cell leukemia/lymphoma. Strongyloidiasis, a gastrointestinal infection by the helminth Strongyloides stercoralis, and Infective Dermatitis associated with HTLV-1 (IDH), appear to be risk factors for the development of HTLV-1 related diseases. We used high-throughput sequencing to map and quantify the insertion sites of the provirus in order to monitor the clonality of the HTLV-1-infected T-cell population (i.e. the number of distinct clones and abundance of each clone). A newly developed biodiversity estimator called "DivE" was used to estimate the total number of clones in the blood. We found that the major determinant of proviral load in all subjects without leukemia/lymphoma was the total number of HTLV-1-infected clones. Nevertheless, the significantly higher proviral load in patients with strongyloidiasis or IDH was due to an increase in the mean clone abundance, not to an increase in the number of infected clones. These patients appear to be less capable of restricting clone abundance than those with HTLV-1 alone. In patients co-infected with Strongyloides there was an increased degree of oligoclonal expansion and a higher rate of turnover (i.e. appearance and disappearance) of HTLV-1-infected clones. In Strongyloides co-infected patients and those with IDH, proliferation of the most abundant HTLV-1(+) T-cell clones is independent of the genomic environment of the provirus, in sharp contrast to patients with HTLV-1 infection alone. This implies that new selection forces are driving oligoclonal proliferation in Strongyloides co-infection and IDH. We conclude that strongyloidiasis and IDH increase the risk of development of HTLV-1-associated diseases by increasing the rate of infection of new clones and the abundance of existing HTLV-1(+) clones. [less ▲]

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See detailGenome-wide Determinants of Proviral Targeting, Clonal Abundance and Expression in Natural HTLV-1 Infection.
Melamed, Anat; Laydon, Daniel J.; Gillet, Nicolas ULg et al

in PLoS Pathogens (2013), 9(3), 1003271

The regulation of proviral latency is a central problem in retrovirology. We postulate that the genomic integration site of human T lymphotropic virus type 1 (HTLV-1) determines the pattern of expression ... [more ▼]

The regulation of proviral latency is a central problem in retrovirology. We postulate that the genomic integration site of human T lymphotropic virus type 1 (HTLV-1) determines the pattern of expression of the provirus, which in turn determines the abundance and pathogenic potential of infected T cell clones in vivo. We recently developed a high-throughput method for the genome-wide amplification, identification and quantification of proviral integration sites. Here, we used this protocol to test two hypotheses. First, that binding sites for transcription factors and chromatin remodelling factors in the genome flanking the proviral integration site of HTLV-1 are associated with integration targeting, spontaneous proviral expression, and in vivo clonal abundance. Second, that the transcriptional orientation of the HTLV-1 provirus relative to that of the nearest host gene determines spontaneous proviral expression and in vivo clonal abundance. Integration targeting was strongly associated with the presence of a binding site for specific host transcription factors, especially STAT1 and p53. The presence of the chromatin remodelling factors BRG1 and INI1 and certain host transcription factors either upstream or downstream of the provirus was associated respectively with silencing or spontaneous expression of the provirus. Cells expressing HTLV-1 Tax protein were significantly more frequent in clones of low abundance in vivo. We conclude that transcriptional interference and chromatin remodelling are critical determinants of proviral latency in natural HTLV-1 infection. [less ▲]

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