References of "Willems, Luc"
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See detailPhysiological and bio-functional properties of gum arabic: a notable interest for certain human diseases
Eloundou Mballa, Pierre; Goffin, Dorothée ULg; Destain, Jacqueline ULg et al

in Biotechnologie, Agronomie, Société et Environnement = Biotechnology, Agronomy, Society and Environment [=BASE] (in press)

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See detailRates of CTL Killing in Persistent Viral Infection In Vivo
Elemans, Marjet; Florins, Arnaud; Willems, Luc ULg et al

in PLoS Computational Biology (2014), 4

The CD8+ cytotoxic T lymphocyte (CTL) response is an important defence against viral invasion. Although CTL-mediated cytotoxicity has been widely studied for many years, the rate at which virus-infected ... [more ▼]

The CD8+ cytotoxic T lymphocyte (CTL) response is an important defence against viral invasion. Although CTL-mediated cytotoxicity has been widely studied for many years, the rate at which virus-infected cells are killed in vivo by the CTL response is poorly understood. To date the rate of CTL killing in vivo has been estimated for three virus infections but the estimates differ considerably, and killing of HIV-1-infected cells was unexpectedly low. This raises questions about the typical anti-viral capability of CTL and whether CTL killing is abnormally low in HIV-1. We estimated the rate of killing of infected cells by CD8+ T cells in two distinct persistent virus infections: sheep infected with Bovine Leukemia Virus (BLV) and humans infected with Human T Lymphotropic Virus type 1 (HTLV-1) which together with existing data allows us to study a total of five viruses in parallel. Although both BLV and HTLV-1 infection are characterised by large expansions of chronically activated CTL with immediate effector function ex vivo and no evidence of overt immune suppression, our estimates are at the lower end of the reported range. This enables us to put current estimates into perspective and shows that CTL killing of HIV-infected cells may not be atypically low. The estimates at the higher end of the range are obtained in more manipulated systems and may thus represent the potential rather than the realised CTL efficiency. [less ▲]

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See detailInteractions between new phenolic glycolipids and model membrane
Sainvitu, Pauline ULg; Nasir, Mehmet Nail ULg; Crowet, Jean-Marc ULg et al

Poster (2014, February 07)

Model membrane based on phospholipids (PL) layers are useful to mimic properties of plasma membranes. The interactions between new synthesized phenolic glycolipids (PGL) and biological membrane are ... [more ▼]

Model membrane based on phospholipids (PL) layers are useful to mimic properties of plasma membranes. The interactions between new synthesized phenolic glycolipids (PGL) and biological membrane are crucial to determine their potential as drug candidates and their cytotoxicity . [less ▲]

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See detailEpigenetic modulators mitigate angiogenesis through a complex transcriptomic network
Shiva Shankar, T.V.; Willems, Luc ULg

in Vascular Pharmacology (2014), 60

In this review, we summarize the knowledge pertaining to the role of epigenetics in the regulation of angiogenesis. In particular, we show that lysine acetylation and cytosine methylation are important ... [more ▼]

In this review, we summarize the knowledge pertaining to the role of epigenetics in the regulation of angiogenesis. In particular, we show that lysine acetylation and cytosine methylation are important transcriptional regulators of angiogenic genes in endothelial cells. Lysine acetylation and cytosine methylation inhibitors idiosyncratically tune the transcriptome and affect expression of key modulators of angiogenesis such as VEGF and eNOS. Transcriptomic profiling also reveals a series of novel genes that are concomitantly affected by epigenetic modulators. The reversibility and overall tolerability of currently available epigenetic inhibitors open up the prospect of therapeutic intervention in pathologies where angiogenesis is exacerbated. This type of multitargeted strategy has the major advantage of overcoming the compensatory feedback mechanisms that characterize single anti-angiogenic factors. [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 detailCheckpoints modulation by the Human T-lymphotropic virus type 1 Tax protein
Carpentier, Alexandre ULg; Barez, Pierre-Yves ULg; Boxus, Mathieu et al

in Retrovirology (2014), 11(S1), 90

HTLV-1 is responsible for two main diseases, Adult T-cell Leukemia/Lymphoma and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis, for which there is currently no satisfactory treatment. Among the ... [more ▼]

HTLV-1 is responsible for two main diseases, Adult T-cell Leukemia/Lymphoma and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis, for which there is currently no satisfactory treatment. Among the proteins encoded by HTLV-1, Tax appears to play an important role in the mechanisms leading to pathogenicity. We are interested in the mechanisms of cell transformation by Tax and more particularly in the interplay between the viral Tax oncoprotein and the DNA damage response (DDR). We demonstrated that transient expression of Tax results in DNA damage, cell cycle arrest and activation of the DDR. In fibroblasts, cell cycle arrest occurs at the G1 and G2 phases depending on the p53 background. Although Tax induces apoptosis and senescence in fibroblasts, HTLV-1 infected lymphocytes proliferate continuously and appear to be adapted to the checkpoint control. This mechanism allows infected lymphocytes to proliferate despite the presence of genomic lesions. With these observations, we propose a novel therapeutic approach based on the principle of synthetic lethality. [less ▲]

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See detailThe Tax protein and the minichromosome maintenance protein complex MCM2-7 affect cell replication and viral transcription
Barez, Pierre-Yves ULg; Carpentier, Alexandre ULg; Boxus, Mathieu et al

in Retrovirology (2014), 11(S1), 96

The Tax oncoprotein plays a key role in the mechanisms of transformation, viral persistence and pathogenicity. Recently, we showed that Tax interacts with the minichromosome maintenance MCM2-7 helicase ... [more ▼]

The Tax oncoprotein plays a key role in the mechanisms of transformation, viral persistence and pathogenicity. Recently, we showed that Tax interacts with the minichromosome maintenance MCM2-7 helicase and binds to origins of DNA replication (Boxus et al, 2012 Blood 119:151). In fact, Tax modulates the spatiotemporal program of origin activation during the S phase of cell cycle. By this mechanism, Tax accelerates S phase progression through early firing of late replication origins. By interacting with the 5’ LTR, the MCM2-7 complex also modulates Tax transactivation. Together, our data thus demonstrates that interaction between Tax and MCM2-7 modulates reprogramming of replication origins as well as viral transcription. [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 detailRole of MCM proteins in HTLV-1 transcription
Barez, Pierre-Yves ULg; Carpentier, Alexandre ULg; Boxus, Mathieu et al

Conference (2013, December 13)

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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 detailThe role of epigenetics in malignant pleural mesothelioma
Vandermeers, Fabian; Neelature Sriramareddy, Sathya; Chrisostome, Costa et al

in Lung Cancer (2013), 81

Malignant pleural mesothelioma (MPM) is an almost invariably fatal cancer of the pleura due to asbestos exposure. Increasing evidence indicates that unresponsiveness to chemotherapy is due to epigenetic ... [more ▼]

Malignant pleural mesothelioma (MPM) is an almost invariably fatal cancer of the pleura due to asbestos exposure. Increasing evidence indicates that unresponsiveness to chemotherapy is due to epigenetic errors leading to inadequate gene expression in tumor cells. The availability of compounds that modulate epigenetic modifications, such as histone acetylation or DNA methylation, offers new prospects for treatment of MPM. Here, we review latest findings on epigenetics in mesothelioma and present novel strategies for promising epigenetic thérapies. [less ▲]

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See detailAcetylation at lysine 346 controls the transforming activity of the HTLV-1 Tax oncoprotein in the Rat-1 fibroblast model
Lodewick, Julie; Sampaio, Carla; Boxus, Mathieu et al

in Retrovirology (2013), 2013(10), 75

Background Transformation by the Tax oncoprotein of the human T cell leukemia virus type 1 (HTLV-1) is governed by actions on cellular regulatory signals, including modulation of specific cellular gene ... [more ▼]

Background Transformation by the Tax oncoprotein of the human T cell leukemia virus type 1 (HTLV-1) is governed by actions on cellular regulatory signals, including modulation of specific cellular gene expression via activation of signaling pathways, acceleration of cell cycle progression via stimulation of cyclin-dependent kinase activity leading to retinoblastoma protein (pRb) hyperphosphorylation and perturbation of survival signals. These actions control early steps in T cell transformation and development of Adult T cell leukemia (ATL), an aggressive malignancy of HTLV-1 infected T lymphocytes. Post-translational modifications of Tax by phosphorylation, ubiquitination, sumoylation and acetylation have been implicated in Tax-mediated activation of the NF-B pathway, a key function associated with Tax transforming potential. Results In this study, we demonstrate that acetylation at lysine K346 in the carboxy-terminal domain of Tax is modulated in the Tax nuclear bodies by the acetyltransferase p300 and the deacetylases HDAC5/7 and controls phosphorylation of the tumor suppressor pRb by Tax-cyclin D3-CDK4-p21CIP complexes. This property correlates with the inability of the acetylation deficient K346R mutant, but not the acetylation mimetic K346Q mutant, to promote anchorage-independent growth of Rat-1 fibroblasts. By contrast, acetylation at lysine K346 had no effects on the ability of Tax carboxy-terminal PDZ-binding domain to interact with the tumor suppressor hDLG. Conclusions The identification of the acetyltransferase p300 and the deacetylase HDAC7 as enzymes modulating Tax acetylation points to new therapeutic targets for the treatment of HTLV-1 infected patients at risk of developing ATL. [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 detailNovel phenolic glycolipids: antioxidant activity and effect on membrane models
Sainvitu, Pauline ULg; Nasir, Mehmet Nail ULg; Draguet, Florian et al

Poster (2013, May 30)

Aromatic glycolipids are of both medical as well as pharmaceutical interest. Antimicrobial, antiviraland antiinflammatory activities have been reported (Otto, 2000, Journal of Molecular Catalysis B ... [more ▼]

Aromatic glycolipids are of both medical as well as pharmaceutical interest. Antimicrobial, antiviraland antiinflammatory activities have been reported (Otto, 2000, Journal of Molecular Catalysis B: Enzymatic). Moreover, they are expected to have interesting antioxidant properties when they contain phenolic groups. The alkyl chain should enhance their ability to penetrate into the cellular membrane (Nicolosi, 2002, Journal of Molecular Catalysis B: Enzymatic). The presence of a sugar unit could also be useful to target specific cells. In this study, novel aromatic glycolipids were synthesized as useful models for studying the structure–activity relationship, in particular as regards to their aromatic group.Theireffect on cell viability when an oxidative stress is induced was tested. In parallel, their interaction with cell models (liposomes) was studied through membrane fusion and permeability experiments. [less ▲]

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See detailBiophysical characterization of the interaction of novel aromatic glycolipid surfactants with membrane models.
Sainvitu, Pauline ULg; Nasir, Mehmet Nail ULg; Draguet, Florian et al

Poster (2013, May 15)

Aromatic glycolipids are of both medical and pharmaceutical interest. Antimicrobial, antiviral and anti-inflammatory activities have been reported (Otto, 2000, Journal of Molecular Catalysis B: Enzymatic ... [more ▼]

Aromatic glycolipids are of both medical and pharmaceutical interest. Antimicrobial, antiviral and anti-inflammatory activities have been reported (Otto, 2000, Journal of Molecular Catalysis B: Enzymatic). Moreover, they are expected to have interesting antioxidant properties when they contain phenolic groups. The alkyl chain should enhance their ability to penetrate into the cellular membrane (Nicolosi, 2002, Journal of Molecular Catalysis B: Enzymatic). The presence of a sugar unit could also be useful to target specific cells. In this study, novel aromatic glycolipids were synthesized as useful models for studying the structure–activity relationship, in particular as a function of their aromatic group. Their interaction with membranes was studied with monolayer models and was predicted by a computational approach. The relationships between these data and their cytotoxicity and antioxidant properties evaluated on cell cultures are discussed. [less ▲]

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See detailBiophysical characterization of the interaction of novel aromatic glycolipid surfactants with membrane models.
Sainvitu, Pauline ULg; Nasir, Mehmet Nail ULg; Nott, Katherine ULg et al

in World Academy of Science, Engineering and Technology (2013, May), 77

Aromatic glycolipids are of both medical and pharmaceutical interest. Antimicrobial, antiviral and anti-inflammatory activities have been reported (Otto, 2000, Journal of Molecular Catalysis B: Enzymatic ... [more ▼]

Aromatic glycolipids are of both medical and pharmaceutical interest. Antimicrobial, antiviral and anti-inflammatory activities have been reported (Otto, 2000, Journal of Molecular Catalysis B: Enzymatic). Moreover, they are expected to have interesting antioxidant properties when they contain phenolic groups. The alkyl chain should enhance their ability to penetrate into the cellular membrane (Nicolosi, 2002, Journal of Molecular Catalysis B: Enzymatic). The presence of a sugar unit could also be useful to target specific cells. In this study, novel aromatic glycolipids were synthesized as useful models for studying the structure–activity relationship, in particular as a function of their aromatic group. Their interaction with membranes was studied with monolayer models and was predicted by a computational approach. The relationships between these data and their cytotoxicity and antioxidant properties evaluated on cell cultures are discussed. [less ▲]

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See detailBiophysical characterization of the interaction of novel aromatic glycolipid surfactants with membrane models.
Sainvitu, Pauline ULg; Nasir, Mehmet Nail ULg; Nott, Katherine ULg et al

in World Academy of Science, Engineering and Technology (2013, May), 77

Aromatic glycolipids are of both medical and pharmaceutical interest. Antimicrobial, antiviral and anti-inflammatory activities have been reported (Otto, 2000, Journal of Molecular Catalysis B: Enzymatic ... [more ▼]

Aromatic glycolipids are of both medical and pharmaceutical interest. Antimicrobial, antiviral and anti-inflammatory activities have been reported (Otto, 2000, Journal of Molecular Catalysis B: Enzymatic). Moreover, they are expected to have interesting antioxidant properties when they contain phenolic groups. The alkyl chain should enhance their ability to penetrate into the cellular membrane (Nicolosi, 2002, Journal of Molecular Catalysis B: Enzymatic). The presence of a sugar unit could also be useful to target specific cells. In this study, novel aromatic glycolipids were synthesized as useful models for studying the structure–activity relationship, in particular as a function of their aromatic group. Their interaction with membranes was studied with monolayer models and was predicted by a computational approach. The relationships between these data and their cytotoxicity and antioxidant properties evaluated on cell cultures are discussed. [less ▲]

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See detailViruses and Cancer
Barez, Pierre-Yves ULg; Carpentier, Alexandre ULg; Willems, Luc ULg

Conference (2013, February 08)

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See detailInteraction of HTLV-­1 Tax with minichromosome maintenance proteins accelerates the replication timing program
Carpentier, Alexandre ULg; Barez, Pierre-Yves ULg; Willems, Luc ULg

Conference (2013, January 28)

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects about twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases among which the most common are the ... [more ▼]

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects about twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases among which the most common are the adult T-cell leukemia (ATL) and a neurodegenerative disorder called HAM/TSP (Human associated myelopathy/ Tropical spastic paraparesis). A key parameter of HTLV-1 pathogenesis is faster replication of provirus-carrying lymphocytes allowing clonal expansion of infected cell populations. The virally-encoded Tax oncoprotein plays an essential role in this process by interacting with DNA replication origins and accelerating S phase progression. By reprogramming the timing of origin firing, Tax also creates a replicative stress leading to DNA double strand breaks. This mechanism further triggers the DNA damage response (DDR) that induces cell cycle arrest and initiates either apoptosis or senescence. However, HTLV-1 infected cells have developed strategies to interfere with the DDR and are adapted to checkpoint control. These cells are thus able to proliferate despite occurrence of DNA damage. Based on these observations, we now propose a novel therapeutic approach based on the principle of synthetic lethality. [less ▲]

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See detailWIP1 deficiency inhibits HTLV-1 Tax oncogenesis: novel therapeutic prospects for treatment of ATL?
Gillet, Nicolas ULg; Carpentier, Alexandre ULg; Barez, Pierre-Yves ULg et al

in Retrovirology (2012), 9(1), 115

Attenuation of p53 activity appears to be a major step in Human T-lymphotropic virus type 1 (HTLV-1) Tax transformation. However, p53 genomic mutations are late and rather infrequent events in HTLV-1 ... [more ▼]

Attenuation of p53 activity appears to be a major step in Human T-lymphotropic virus type 1 (HTLV-1) Tax transformation. However, p53 genomic mutations are late and rather infrequent events in HTLV-1 induced Adult T cell leukemia (ATL). The paper by Zane et al. shows that a mediator of p53 activity, Wild-type p53-induced phosphatase 1 (Wip1), contributes to Tax-induced oncogenesis in a mouse model. Wip1 may therefore be a novel target for therapeutic approaches. [less ▲]

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