References of "Asquith, Becca"
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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 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 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 detailSafety of long-term treatment of HAM/TSP patients with valproic acid
Olindo, Stéphane; Belrose, Gildas; Gillet, Nicolas ULg et al

in Blood (2011), 118(24), 6306-6309

HTLV-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a neurodegenerative disease of the central nervous system induced by Human T lymphotropic virus type 1 (HTLV-1). As a potential ... [more ▼]

HTLV-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a neurodegenerative disease of the central nervous system induced by Human T lymphotropic virus type 1 (HTLV-1). As a potential therapeutic approach, we previously suggested reducing the proviral load (PVL) by modulating lysine deacetylase activity using valproic acid (VPA) and exposing virus-positive cells to the host immune response. We conducted a single-center, two-year open-label trial, with 19 HAM/TSP volunteers treated with oral VPA. PVL, CD38/HLA-DR expression and CD8+ lysis efficiency were not significantly affected by VPA. Mean scores of HAM/TSP disability did not differ between baseline and final visit. Walking Time Test (WTT) increased significantly (>20%) in 3 patients and was in keeping with minor VPA side effects (drowsiness and tremor). WTT improved rapidly after VPA discontinuation. We conclude that long term treatment with VPA is safe in HAM/TSP. [less ▲]

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See detailGene activation therapy: from the BLV model to HAM/TSP patients.
Lezin, Agnes; Olindo, Stephane; Belrose, Gildas et al

in Frontiers in Bioscience (Scholar Edition) (2009), 1

HTLV-1 (human T-lymphotropic virus type 1) and BLV (bovine leukemia virus) are two related retroviruses infecting CD4+ and B lymphocytes in humans and ruminants, respectively. During infection, the host ... [more ▼]

HTLV-1 (human T-lymphotropic virus type 1) and BLV (bovine leukemia virus) are two related retroviruses infecting CD4+ and B lymphocytes in humans and ruminants, respectively. During infection, the host-pathogen interplay is characterized by very dynamic kinetics resulting in equilibrium between the virus, which attempts to proliferate, and the immune response, which seeks to exert tight control of the virus. A major determinant of disease induction by both viruses is the accumulation of provirus in peripheral blood. In the absence of viral proteins, virus infected cells escape recognition and destruction by the host immune response. We propose a novel therapeutic strategy based on transient activation of viral expression using epigenetic modulators; this exposes infected cells to the immune response and results in significant reductions in proviral loads. In the absence of satisfactory therapies, this viral gene-activation strategy might delay progression, or even be curative, for HTLV-1 induced myelopathy / tropical spastic paraparesis (HAM/TSP). [less ▲]

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See detailEarlier onset of delta-retrovirus-induced leukemia after splenectomy.
Florins, ARNAUD-FRANCOIS ULg; Reichert, Michal; Asquith, Becca et al

in PLoS ONE (2009), 4(9), 6943

Infection by delta-retroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) is mostly asymptomatic. Indeed, only a minority (<5%) of delta-retrovirus infected hosts ... [more ▼]

Infection by delta-retroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) is mostly asymptomatic. Indeed, only a minority (<5%) of delta-retrovirus infected hosts will develop either lymphoproliferative or neurodegenerative diseases after long latency periods. In fact, the host immune response is believed to tightly control viral replication but this assumption has not been definitely proven in vivo. Here, we provide direct experimental evidence demonstrating that integrity of the spleen is required to control pathogenesis. In the BLV model, we show that asplenia decreases efficiency of the immune response and induces an imbalance in cell dynamics resulting in accelerated onset of leukemia. These observations enlighten a potential threat in splenectomized HTLV-1 carriers and justify a regular preventive evaluation. [less ▲]

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See detailReduction of B cell turnover in chronic lymphocytic leukaemia.
Defoiche, Julien; Debacq, Christophe; Asquith, Becca et al

in British Journal of Haematology (2008), 143(2), 240-7

Whether chronic lymphocytic leukaemia (CLL) is a latent or a proliferating disease has been intensively debated. Whilst the dogma that CLL results from accumulation of dormant lymphocytes is supported by ... [more ▼]

Whether chronic lymphocytic leukaemia (CLL) is a latent or a proliferating disease has been intensively debated. Whilst the dogma that CLL results from accumulation of dormant lymphocytes is supported by the unresponsiveness of leukaemic cells to antigens and polyclonal activators, recent in vivo kinetic measurements indicate that B lymphocytes do divide at significant rates in CLL. However, an important and still unanswered question is whether CLL cells proliferate faster or slower compared with their normal counterparts. This report addressed directly this point and compared B-cell kinetics in CLL subjects and healthy controls, using a pulse-chase approach based on incorporation of deuterium from 6,6-(2)H(2)-glucose into DNA. We confirmed that B cells proliferated at significant levels in CLL but found that the proliferation rates were reduced compared with healthy subjects (mean 0.47 vs. 1.31%/d respectively, P = 0.007), equivalent to an extended doubling time of circulating B cells (147 d vs. 53 d). In conclusion, CLL B cells proliferate at reduced levels compared with healthy controls. CLL is thus characterized by an aberrant B-cell kinetics with a decrease in cell turnover, an observation that may impact on elaboration of efficient therapeutic strategies. [less ▲]

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See detailCell dynamics and immune response to BLV infection: a unifying model
Florins, Arnaud-Francois ULg; Gillet, Nicolas ULg; Asquith, Becca et al

in Frontiers in Bioscience : A Journal and Virtual Library (2007), 12

Bovine Leukemia virus (BLV) is the natural etiological agent of a lymphoproliferative disease in cattle. BLV can also be transmitted experimentally to a related ruminant species, sheep, in which the ... [more ▼]

Bovine Leukemia virus (BLV) is the natural etiological agent of a lymphoproliferative disease in cattle. BLV can also be transmitted experimentally to a related ruminant species, sheep, in which the pathogenesis is more acute. Although both susceptible species develop a strong anti-viral immune response, the virus persists indefinitely throughout life, apparently at a transcriptionally silent stage, at least in a proportion of infected cells. Soon after infection, these humoral and cytotoxic activities very efficiently abolish the viral replicative cycle, permitting only mitotic expansion of provirus-carrying cells. Short term cultures of these infected cells initially indicated that viral expression protects against spontaneous apoptosis, suggesting that leukemia is a process of accumulation of long-lived cells. This conclusion was recently reconsidered following in vivo dynamic studies based on perfusions of nucleoside (bromodeoxyuridine) or fluorescent protein markers (CFSE). In sheep, the turnover rate of infected cells is increased, suggesting that a permanent clearance process is exerted by the immune system. Lymphocyte trafficking from and to the secondary lymphoid organs is a key component in the maintenance of cell homeostasis. The net outcome of the immune selective pressure is that only cells in which the virus is transcriptionally silenced survive and accumulate, ultimately leading to lymphocytosis. Activation of viral and/or cellular expression in this silent reservoir with deacetylase inhibitors causes the collapse of the proviral loads. In other words, modulation of viral expression appears to be curative in lymphocytic sheep, an approach that might also be efficient in patients infected with the related Human T-lymphotropic virus type 1. In summary, a dynamic interplay between BLV and the host immune response modulates a complex equilibrium between (i) viral expression driving (or) favoring proliferation and (ii) viral silencing preventing apoptosis. As conclusion, we propose a hypothetical model unifying all these mechanisms. [less ▲]

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See detailHistone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients.
Lezin, Agnes; Gillet, Nicolas ULg; Olindo, Stephane et al

in Blood (2007), 110(10), 3722-8

Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated ... [more ▼]

Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A major determinant of disease progression is increased peripheral blood proviral load (PVL), possibly via the accumulation of infected cells in the central nervous system (CNS) creating a damaging inflammatory response. Current therapeutic approaches that focus on reducing either cell proliferation, viral replication, or tissue invasion are still unsatisfactory. Contrasting with these inhibitory strategies, we evaluated the efficacy of a novel approach aimed, paradoxically, at activating viral gene expression to expose virus-positive cells to the host immune response. We used valproate (VPA), a histone deacetylase inhibitor that has been used for decades as a chronic, safe treatment for epileptic disorders. Based on in vitro and in vivo data, we provide evidence that transient activation of the latent viral reservoir causes its collapse, a process that may alleviate the condition of HAM/TSP. This represents the first such approach to treating HAM/TSP, using gene activation therapy to tilt the host-pathogen balance in favor of an existing antiviral response. This trial is registered at http://clinicaltrials.gov/as no. NCT00519181. [less ▲]

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See detailPeripheral blood B-cell death compensates for excessive proliferation in lymphoid tissues and maintains homeostasis in bovine leukemia virus-infected sheep.
Debacq, Christophe; Gillet, Nicolas ULg; Asquith, Becca et al

in Journal of Virology (2006), 80(19), 9710-9719

The size of a lymphocyte population is primarily determined by a dynamic equilibrium between cell proliferation and death. Hence, lymphocyte recirculation between the peripheral blood and lymphoid tissues ... [more ▼]

The size of a lymphocyte population is primarily determined by a dynamic equilibrium between cell proliferation and death. Hence, lymphocyte recirculation between the peripheral blood and lymphoid tissues is a key determinant in the maintenance of cell homeostasis. Insights into these mechanisms can be gathered from large-animal models, where lymphatic cannulation from individual lymph nodes is possible. In this study, we assessed in vivo lymphocyte trafficking in bovine leukemia virus (BLV)-infected sheep. With a carboxyfluorescein diacetate succinimidyl ester labeling technique, we demonstrate that the dynamics of lymphocyte recirculation is unaltered but that accelerated proliferation in the lymphoid tissues is compensated for by increased death in the peripheral blood cell population. Lymphocyte homeostasis is thus maintained by biphasic kinetics in two distinct tissues, emphasizing a very dynamic process during BLV infection. [less ▲]

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See detailSpleen-dependent turnover of CD11b peripheral blood B lymphocytes in bovine leukemia virus-infected sheep.
Florins, Arnaud-Francois ULg; Gillet, Nicolas ULg; Asquith, Becca et al

in Journal of virology (2006), 80(24), 11998-2008

Lymphocyte homeostasis is determined by a critical balance between cell proliferation and death, an equilibrium which is deregulated in bovine leukemia virus (BLV)-infected sheep. We have previously shown ... [more ▼]

Lymphocyte homeostasis is determined by a critical balance between cell proliferation and death, an equilibrium which is deregulated in bovine leukemia virus (BLV)-infected sheep. We have previously shown that an excess of proliferation occurs in lymphoid tissues and that the peripheral blood population is prone to increased cell death. To further understand the mechanisms involved, we evaluated the physiological role of the spleen in this accelerated turnover. To this end, B lymphocytes were labeled in vivo using a fluorescent marker (carboxyfluorescein diacetate succinimidyl ester), and the cell kinetic parameters (proliferation and death rates) of animals before and after splenectomy were compared. We show that the enhanced cell death observed in BLV-infected sheep is abrogated after splenectomy, revealing a key role of the spleen in B-lymphocyte dynamics. [less ▲]

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See detailQuantifying lymphocyte kinetics in vivo using carboxyfluorescein diacetate succinimidyl ester (CFSE).
Asquith, Becca; Debacq, Christophe; Florins, Arnaud-Francois ULg et al

in Proceedings of the Royal Society B : Biological Sciences (2006), 273(1590), 1165-71

The cytoplasmic dye carboxyfluorescein diacetate succinimidyl ester (CFSE) is used to quantify cell kinetics. It is particularly important in studies of lymphocyte homeostasis where its labelling of cells ... [more ▼]

The cytoplasmic dye carboxyfluorescein diacetate succinimidyl ester (CFSE) is used to quantify cell kinetics. It is particularly important in studies of lymphocyte homeostasis where its labelling of cells irrespective of their stage in the cell cycle makes it preferable to deuterated glucose and BrdU, which only label dividing cells and thus produce unrepresentative results. In the past, experiments have been limited by the need to obtain a clear separation of CFSE peaks forcing scientists to adopt a strategy of in vitro labelling of cells followed by their injection into the host. Here we develop a framework for analysis of in vivo CFSE labelling data. This enables us to estimate the rate of proliferation and death of lymphocytes in situ, and thus represents a considerable advance over current procedures. We illustrate this approach using in vivo CFSE labelling of B lymphocytes in sheep. [less ▲]

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See detailReduced cell turnover in lymphocytic monkeys infected by human T-lymphotropic virus type 1.
Debacq, Christophe; Heraud, Jean-Michel; Asquith, Becca et al

in Oncogene (2005), 24(51), 7514-23

Understanding cell dynamics in animal models have implications for therapeutic strategies elaborated against leukemia in human. Quantification of the cell turnover in closely related primate systems is ... [more ▼]

Understanding cell dynamics in animal models have implications for therapeutic strategies elaborated against leukemia in human. Quantification of the cell turnover in closely related primate systems is particularly important for rare and aggressive forms of human cancers, such as adult T-cell leukemia. For this purpose, we have measured the death and proliferation rates of the CD4+ T lymphocyte population in squirrel monkeys (Saimiri sciureus) infected by human T-lymphotropic virus type 1 (HTLV-1). The kinetics of in vivo bromodeoxyuridine labeling revealed no modulation of the cell turnover in HTLV-1-infected monkeys with normal CD4 cell counts. In contrast, a substantial decrease in the proliferation rate of the CD4+ T population was observed in lymphocytic monkeys (e.g. characterized by excessive proportions of CD4+ T lymphocytes and by the presence of abnormal flower-like cells). Unexpectedly, onset of HTLV-associated leukemia thus occurs in the absence of increased CD4+ T-cell proliferation. This dynamics significantly differs from the generalized activation of the T-cell turnover induced by other primate lymphotropic viruses like HIV and SIV. [less ▲]

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