Imperial College London

Dr Becca Asquith

Faculty of MedicineDepartment of Infectious Disease

Professor of Mathematical Immunology
 
 
 
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Contact

 

+44 (0)20 7594 3731b.asquith

 
 
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Location

 

112Wright Fleming WingSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

101 results found

Laydon DJ, Sunkara V, Boelen L, Bangham CRM, Asquith Bet al., 2020, The relative contributions of infectious and mitotic spread to HTLV-1 persistence, PLoS Computational Biology, Vol: 16, ISSN: 1553-734X

Human T-lymphotropic virus type-1 (HTLV-1) persists within hosts via infectious spread (de novo infection) and mitotic spread (infected cell proliferation), creating a population structure of multiple clones (infected cell populations with identical genomic proviral integration sites). The relative contributions of infectious and mitotic spread to HTLV-1 persistence are unknown, and will determine the efficacy of different approaches to treatment. The prevailing view is that infectious spread is negligible in HTLV-1 persistence beyond early infection. However, in light of recent high-throughput data on the abundance of HTLV-1 clones, and recent estimates of HTLV-1 clonal diversity that are substantially higher than previously thought (typically between 104 and 105 HTLV-1+ T cell clones in the body of an asymptomatic carrier or patient with HTLV-1-associated myelopathy/tropical spastic paraparesis), ongoing infectious spread during chronic infection remains possible. We estimate the ratio of infectious to mitotic spread using a hybrid model of deterministic and stochastic processes, fitted to previously published HTLV-1 clonal diversity estimates. We investigate the robustness of our estimates using three alternative estimators. We find that, contrary to previous belief, infectious spread persists during chronic infection, even after HTLV-1 proviral load has reached its set point, and we estimate that between 100 and 200 new HTLV-1 clones are created and killed every day. We find broad agreement between all estimators. The risk of HTLV-1-associated malignancy and inflammatory disease is strongly correlated with proviral load, which in turn is correlated with the number of HTLV-1-infected clones, which are created by de novo infection. Our results therefore imply that suppression of de novo infection may reduce the risk of malignant transformation.

Journal article

Costa Del Amo P, Debebe B, Razavi-Mohseni M, Nakaoka S, Worth A, Wallace D, Beverley P, Macallan D, Asquith Bet al., 2020, The rules of human T cell fate in vivo, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224

The processes governing lymphocyte fate (division, differentiation, and death), are typically assumed to be independent of cell age. This assumption has been challenged by a series of elegant studies which clearly show that, for murine cells in vitro, lymphocyte fate is age-dependent and that younger cells (i.e., cells which have recently divided) are less likely to divide or die. Here we investigate whether the same rules determine human T cell fate in vivo. We combined data from in vivo stable isotope labeling in healthy humans with stochastic, agent-based mathematical modeling. We show firstly that the choice of model paradigm has a large impact on parameter estimates obtained using stable isotope labeling i.e., different models fitted to the same data can yield very different estimates of T cell lifespan. Secondly, we found no evidence in humans in vivo to support the model in which younger T cells are less likely to divide or die. This age-dependent model never provided the best description of isotope labeling; this was true for naïve and memory, CD4+ and CD8+ T cells. Furthermore, this age-dependent model also failed to predict an independent data set in which the link between division and death was explored using Annexin V and deuterated glucose. In contrast, the age-independent model provided the best description of both naïve and memory T cell dynamics and was also able to predict the independent dataset.

Journal article

Debebe BJ, Boelen L, Lee JC, IAVI Protocol C Investigators, Thio CL, Astemborski J, Kirk G, Khakoo SI, Donfield SM, Goedert JJ, Asquith Bet al., 2020, Identifying the immune interactions underlying HLA class I disease associations, eLife, Vol: 9, ISSN: 2050-084X

Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms in the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of 'protective' or 'detrimental' CD8+ T cell responses which are restricted by the host HLA class I allotype. However, given the diverse receptors which are bound by HLA class I molecules, alternative interpretations are possible. As well as binding T cell receptors on CD8+ T cells, HLA class I molecules are important ligands for inhibitory and activating killer immunoglobulin-like receptors (KIRs) which are found on natural killer cells and some T cells; for the CD94:NKG2 family of receptors also expressed mainly by NK cells and for leukocyte immunoglobulin-like receptors (LILRs) on myeloid cells. The aim of this study is to develop an immunogenetic approach for identifying and quantifying the relative contribution of different receptor-ligand interactions to a given HLA class I disease association and then to use this approach to investigate the immune interactions underlying HLA class I disease associations in three viral infections: Human T cell Leukemia Virus type 1, Human Immunodeficiency Virus type 1 and Hepatitis C Virus as well as in the inflammatory condition Crohn's disease.

Journal article

Macallan D, Busch R, Asquith B, 2019, Current estimates of T cell kinetics in humans, Current Opinion in Systems Biology, Vol: 18, Pages: 77-86, ISSN: 2452-3100

Stable isotope labelling is a generally applicable method of quantifying cell dynamics. Its advent has opened up the way for the quantitative study of T cells in humans. However, the literature is confusing as estimates vary by orders of magnitude between studies. In this short review we aim to explain the reasons for the discrepancies in estimates, clarify which estimates have been superseded and why and highlight the current best estimates. We focus on stable isotope labelling of T cell subsets in healthy humans.

Journal article

Boelen L, Debebe B, Silveira M, Salam A, Makinde J, Roberts CH, Wang ECY, Frater J, Gilmour J, Twigger K, Ladell K, Miners KL, Jayaraman J, Traherne JA, Price DA, Qi Y, Martin MP, Macallan DC, Thio CL, Astemborski J, Kirk G, Donfield SM, Buchbinder S, Khakoo SI, Goedert JJ, Trowsdale J, Carrington M, Kollnberger S, Asquith Ret al., 2018, Inhibitory killer-cell immunoglobulin-like receptors strengthen CD8+ T cell-mediated control of HIV-1, HCV and HTLV-1, Science Immunology, Vol: 3, ISSN: 2470-9468

Killer cell immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer cells, where they play a key role in the regulation of innate immune responses. Recent studies show that inhibitory KIRs can also affect adaptive T cell–mediated immunity. In mice and in human T cells in vitro, inhibitory KIR ligation enhanced CD8+ T cell survival. To investigate the clinical relevance of these observations, we conducted an extensive immunogenetic analysis of multiple independent cohorts of HIV-1–, hepatitis C virus (HCV)–, and human T cell leukemia virus type 1 (HTLV-1)–infected individuals in conjunction with in vitro assays of T cell survival, analysis of ex vivo KIR expression, and mathematical modeling of host-virus dynamics. Our data suggest that functional engagement of inhibitory KIRs enhances the CD8+ T cell response against HIV-1, HCV, and HTLV-1 and is a significant determinant of clinical outcome in all three viral infections.

Journal article

Costa del Amo P, Lahoz-Beneytez J, Boelen L, Ahmed R, Miners KL, Zhang Y, Roger L, Jones RE, Fuertes Marraco SA, Speiser DE, Baird DM, Price DA, Ladell K, Macallan D, Asquith Bet al., 2018, Human TSCM cell dynamics in vivo are compatible with long-lived immunological memory and stemness, PLoS Biology, Vol: 16, ISSN: 1544-9173

Adaptive immunity relies on the generation and maintenance of memory T cells to provide protection against repeated antigen exposure. It has been hypothesised that a self-renewing population of T cells, named stem cell–like memory T (TSCM) cells, are responsible for maintaining memory. However, it is not clear if the dynamics of TSCM cells in vivo are compatible with this hypothesis. To address this issue, we investigated the dynamics of TSCM cells under physiological conditions in humans in vivo using a multidisciplinary approach that combines mathematical modelling, stable isotope labelling, telomere length analysis, and cross-sectional data from vaccine recipients. We show that, unexpectedly, the average longevity of a TSCM clone is very short (half-life < 1 year, degree of self-renewal = 430 days): far too short to constitute a stem cell population. However, we also find that the TSCM population is comprised of at least 2 kinetically distinct subpopulations that turn over at different rates. Whilst one subpopulation is rapidly replaced (half-life = 5 months) and explains the rapid average turnover of the bulk TSCM population, the half-life of the other TSCM subpopulation is approximately 9 years, consistent with the longevity of the recall response. We also show that this latter population exhibited a high degree of self-renewal, with a cell residing without dying or differentiating for 15% of our lifetime. Finally, although small, the population was not subject to excessive stochasticity. We conclude that the majority of TSCM cells are not stem cell–like but that there is a subpopulation of TSCM cells whose dynamics are compatible with their putative role in the maintenance of T cell memory.

Journal article

Nemat-Gorgani N, Hilton HG, Henn BM, Lin M, Gignoux CR, Myrick JW, Werely CJ, Granka JM, Moller M, Hoal EG, Yawata M, Yawata N, Boelen L, Asquith RE, Parham P, Norman PJet al., 2018, Different selected mechanisms attenuated the inhibitory interaction of KIR2DL1 with C2+ HLA-C in two indigenous human populations in Southern Africa, Journal of Immunology, ISSN: 1550-6606

The functions of human NK cells in defense against pathogens and placental development during reproduction are modulated by interactions of killer cell Ig-like receptors (KIRs) with HLA-A, -B and -C class I ligands. Both receptors and ligands are highly polymorphic and exhibit extensive differences between human populations. Indigenous to southern Africa are the KhoeSan, the most ancient group of modern human populations, who have highest genomic diversity worldwide. We studied two KhoeSan populations, the Nama pastoralists and the ≠Khomani San hunter-gatherers. Comprehensive next-generation sequence analysis of HLA-A, -B, and -C and all KIR genes identified 248 different KIR and 137 HLA class I, which assort into ∼200 haplotypes for each gene family. All 74 Nama and 78 ≠Khomani San studied have different genotypes. Numerous novel KIR alleles were identified, including three arising by intergenic recombination. On average, KhoeSan individuals have seven to eight pairs of interacting KIR and HLA class I ligands, the highest diversity and divergence of polymorphic NK cell receptors and ligands observed to date. In this context of high genetic diversity, both the Nama and the ≠Khomani San have an unusually conserved, centromeric KIR haplotype that has arisen to high frequency and is different in the two KhoeSan populations. Distinguishing these haplotypes are independent mutations in KIR2DL1, which both prevent KIR2DL1 from functioning as an inhibitory receptor for C2+ HLA-C. The relatively high frequency of C2+ HLA-C in the Nama and the ≠Khomani San appears to have led to natural selection against strong inhibitory C2-specific KIR.

Journal article

Patel AA, Zhang Y, Fullerton JN, Boelen L, Rongvaux A, Maini AA, Bigley V, Flavell RA, Gilroy DW, Asquith B, Macallan D, Yona Set al., 2017, The fate and lifespan of human monocyte subsets in steady state and systemic inflammation, Journal of Experimental Medicine, Vol: 214, Pages: 1913-1923, ISSN: 0022-1007

In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition. Intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively). In a human experimental endotoxemia model, a transient but profound monocytopenia was observed; restoration of circulating monocytes was achieved by the early release of classical monocytes from bone marrow. The sequence of repopulation recapitulated the order of maturation in healthy homeostasis. This developmental relationship between monocyte subsets was verified by fate mapping grafted human classical monocytes into humanized mice, which were able to differentiate sequentially into intermediate and nonclassical cells.

Journal article

Elemans M, Boelen L, Rasmussen M, Buus S, Asquith Bet al., 2017, HIV-1 adaptation to NK cell-mediated immune pressure, PLOS PATHOGENS, Vol: 13, ISSN: 1553-7366

The observation, by Alter et al., of the enrichment of NK cell “escape” variants in individuals carrying certain Killer-cell Immunoglobulin-like Receptor (KIR) genes is compelling evidence that natural killer (NK) cells exert selection pressure on HIV-1. Alter et al hypothesise that variant peptide, in complex with HLA class I molecules binds KIR receptors and either increases NK cell inhibition or decreases NK cell activation compared to wild type peptide thus leading to virus escape from the NK cell response. According to this hypothesis, in order for NK cells to select for an escape variant, an individual must carry both the KIR and an HLA ligand that binds the variant peptide. In this study we estimate the proportion of the population that is capable of selecting for escape variants and use both epidemiological modelling and a model-free approach to investigate whether this proportion explains the observed variant enrichment. We found that the fraction of individuals within whom the variant would have a selective advantage was low and was unable to explain the high degree of enrichment observed. We conclude that whilst Alter et al’s data is consistent with selection pressure, the mechanism that they postulate is unlikely. The importance of this work is two-fold. Firstly, it forces a re-evaluation of some of the clearest evidence that NK cells exert a protective effect in HIV-1 infection. Secondly, it implies that there is a significant aspect of immunology that is not understood: it is possible that KIRs bind much more widely than was previously appreciated; that a gene in linkage with the KIR genes is responsible for considerable peptide-dependent selection or that variant peptides are indirectly impacting KIR ligation.

Journal article

Lahoz-Beneytez J, Schaller S, Macallan D, Eissing T, Niederalt C, Asquith Bet al., 2017, Physiologically based simulations of deuterated glucose for quantifying cell turnover in humans, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224

In vivo [6,6-2H2]-glucose labeling is a state-of-the-art technique for quantifying cell proliferation and cell disappearance in humans. However, there are discrepancies between estimates of T cell proliferation reported in short (1-day) versus long (7-day) 2H2-glucose studies and very-long (9-week) 2H2O studies. It has been suggested that these discrepancies arise from underestimation of true glucose exposure from intermittent blood sampling in the 1-day study. Label availability in glucose studies is normally approximated by a “square pulse” (Sq pulse). Since the body glucose pool is small and turns over rapidly, the availability of labeled glucose can be subject to large fluctuations and the Sq pulse approximation may be very inaccurate. Here, we model the pharmacokinetics of exogenous labeled glucose using a physiologically based pharmacokinetic (PBPK) model to assess the impact of a more complete description of label availability as a function of time on estimates of CD4+ and CD8+ T cell proliferation and disappearance. The model enabled us to predict the exposure to labeled glucose during the fasting and de-labeling phases, to capture the fluctuations of labeled glucose availability caused by the intake of food or high-glucose beverages, and to recalculate the proliferation and death rates of immune cells. The PBPK model was used to reanalyze experimental data from three previously published studies using different labeling protocols. Although using the PBPK enrichment profile decreased the 1-day proliferation estimates by about 4 and 7% for CD4 and CD8+ T cells, respectively, differences with the 7-day and 9-week studies remained significant. We conclude that the approximations underlying the “square pulse” approach—recently suggested as the most plausible hypothesis—only explain a component of the discrepancy in published T cell proliferation rate estimates.

Journal article

Macallan DC, Borghans JA, Asquith B, 2017, Human T cell memory: a dynamic view., Vaccines, Vol: 5, ISSN: 2076-393X

Long-term T cell-mediated protection depends upon the formation of a pool of memory cells to protect against future pathogen challenge. In this review we argue that looking at T cell memory from a dynamic viewpoint can help in understanding how memory populations are maintained following pathogen exposure or vaccination. For example, a dynamic view resolves the apparent paradox between the relatively short lifespans of individual memory cells and very long-lived immunological memory by focussing on the persistence of clonal populations, rather than individual cells. Clonal survival is achieved by balancing proliferation, death and differentiation rates within and between identifiable phenotypic pools; such pools correspond broadly to sequential stages in the linear differentiation pathway. Each pool has its own characteristic kinetics, but only when considered as a population; single cells exhibit considerable heterogeneity. In humans, we tend to concentrate on circulating cells, but memory T cells in non-lymphoid tissues and bone marrow are increasingly recognised as critical for immune defence; their kinetics, however, remain largely unexplored. Considering vaccination from this viewpoint shifts the focus from the size of the primary response to the survival of the clone and enables identification of critical system pinch-points and opportunities to improve vaccine efficacy.

Journal article

Asquith B, de Boer RJ, 2016, How lymphocytes add up., Nature Immunology, Vol: 18, Pages: 12-13, ISSN: 1529-2916

A surprising molecular mechanism underlying signal integration and programmed proliferation in adaptive immunity has been identified: the cell-cycle regulator Myc enables a lymphocyte to add up the strength of signals it receives and time its response accordingly.

Journal article

Ahmed R, Roger L, Costa Del Amo P, Miners KL, Jones RE, Boelen L, Fali T, Elemans M, Zhang Y, Appay V, Baird DM, Asquith B, Price DA, Macallan DC, Ladell Ket al., 2016, Human stem cell-like memory T cells are maintained in a state of dynamic flux, Cell Reports, Vol: 17, Pages: 2811-2818, ISSN: 2211-1247

Adaptive immunity requires the generation of memory T cells from naive precursors selected in the thymus. The key intermediaries in this process are stem cell-like memory T (TSCM) cells, multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. In theory, antigen specificity within the TSCM pool may be imprinted statically as a function of largely dormant cells and/or retained dynamically by more transitory subpopulations. To explore the origins of immunological memory, we measured the turnover of TSCM cells in vivo using stable isotope labeling with heavy water. The data indicate that TSCM cells in both young and elderly subjects are maintained by ongoing proliferation. In line with this finding, TSCM cells displayed limited telomere length erosion coupled with high expression levels of active telomerase and Ki67. Collectively, these observations show that TSCM cells exist in a state of perpetual flux throughout the human lifespan.

Journal article

Lahoz-Beneytez J, Elemans M, Zhang Y, Ahmed R, Salam A, Block M, Niederalt C, Asquith B, Macallan Det al., 2016, Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives, Blood, Vol: 127, Pages: 3431-3438, ISSN: 0006-4971

Human neutrophils have traditionally been thought to have a short half-life in blood; estimates varyfrom 4-18 hours. This dogma was recently challenged by stable isotope labeling studies with heavywater which yielded estimates in excess of 3 days. To investigate this disparity we generated newstable isotope labeling data in healthy adult subjects using both heavy water (n=4) and deuteriumlabeledglucose (n=9), a compound with more rapid labeling kinetics. To interpret results wedeveloped a novel mechanistic model. We applied this model to both previously-published (n=5) andnewly-generated data. We initially constrained the ratio of the blood neutrophil pool to the marrowprecursor pool (R=0.26, from published values). Analysis of heavy water datasets yielded turnoverrates consistent with a short blood half-life, but parameters, particularly marrow transit-time, werepoorly-defined. Analysis of glucose-labeling data yielded more precise estimates of half-life, 0.79 ±0.25 days (19 hours), and marrow transit-time, 5.80 ± 0.42 days. Substitution of this marrow transittimein the heavy water analysis gave a better-defined blood half-life, 0.77 ± 0.14 days (18.5 hours),close to glucose-derived values. Allowing R to vary yielded a best-fit value, R=0.19. Reanalysis of thepreviously-published model and data also revealed the origin of their long estimates for neutrophilhalf-life, an implicit assumption that R is very large, which is physiologically untenable. We concludethat stable isotope labeling in healthy humans is consistent with a blood neutrophil half-life of lessthan one day.

Journal article

Boelen LP, O'Neill PK, Quigley KJ, Reynolds CJ, Maillere B, Robinson JH, Lertmemongkolchai G, Altmann D, Boyton R, Asquith Ret al., 2016, BIITE: A Tool to Determine HLA Class II Epitopes from T Cell ELISpot Data, PLOS Computational Biology, Vol: 12, ISSN: 1553-734X

Activation of CD4+ T cells requires the recognition of peptides that are presented by HLA class II molecules and can be assessed experimentally using the ELISpot assay. However, even given an individual’s HLA class II genotype, identifying which class II molecule is responsible for a positive ELISpot response to a given peptide is not trivial. The two main difficulties are the number of HLA class II molecules that can potentially be formed in a single individual (3–14) and the lack of clear peptide binding motifs for class II molecules. Here, we present a Bayesian framework to interpret ELISpot data (BIITE: Bayesian Immunogenicity Inference Tool for ELISpot); specifically BIITE identifies which HLA-II:peptide combination(s) are immunogenic based on cohort ELISpot data. We apply BIITE to two ELISpot datasets and explore the expected performance using simulations. We show this method can reach high accuracies, depending on the cohort size and the success rate of the ELISpot assay within the cohort.

Journal article

Asquith RE, 2015, Reconciling estimates of cell proliferation from stable isotope labeling experiments, PLOS Computational Biology, Vol: 11, ISSN: 1553-734X

Stable isotope labeling is the state of the art technique for in vivo quantification of lymphocyte kinetics in humans. It has been central to a number of seminal studies, particularly in the context of HIV-1 and leukemia. However, there is a significant discrepancy between lymphocyte proliferation rates estimated in different studies. Notably, deuterated 2H2-glucose (D2-glucose) labeling studies consistently yield higher estimates of proliferation than deuterated water (D2O) labeling studies. This hampers our understanding of immune function and undermines our confidence in this important technique. Whether these differences are caused by fundamental biochemical differences between the two compounds and/or by methodological differences in the studies is unknown. D2-glucose and D2O labeling experiments have never been performed by the same group under the same experimental conditions; consequently a direct comparison of these two techniques has not been possible. We sought to address this problem. We performed both in vitro and murine in vivo labeling experiments using identical protocols with both D2-glucose and D2O. This showed that intrinsic differences between the two compounds do not cause differences in the proliferation rate estimates, but that estimates made using D2-glucose in vivo were susceptible to difficulties in normalization due to highly variable blood glucose enrichment. Analysis of three published human studies made using D2-glucose and D2O confirmed this problem, particularly in the case of short term D2-glucose labeling. Correcting for these inaccuracies in normalization decreased proliferation rate estimates made using D2-glucose and slightly increased estimates made using D2O; thus bringing the estimates from the two methods significantly closer and highlighting the importance of reliable normalization when using this technique.

Journal article

Laydon DJ, Sunkara V, Bangham CRM, Asquith Bet al., 2015, Estimating rates of de novo infection and mitotic replication in HTLV-1 persistence: de novo infection continues after early infection, RETROVIROLOGY, Vol: 12, ISSN: 1742-4690

Journal article

Asquith RE, Laydon D, Bangham C, 2015, Estimating T-cell repertoire diversity: limitations of classical estimators and a new approach, Philosophical Transactions of the Royal Society B: Biological Sciences, Vol: 370, ISSN: 1471-2970

A highly diverse T-cell receptor (TCR) repertoire is a fundamental property of an effective immune system, and is associated with efficient control of viral infections and other pathogens. However, direct measurement of total TCR diversity is impossible. The diversity is high and the frequency distribution of individual TCRs is heavily skewed; the diversity therefore cannot be captured in a blood sample. Consequently, estimators of the total number of TCR clonotypes that are present in the individual, in addition to those observed, are essential. This is analogous to the ‘unseen species problem’ in ecology. We review the diversity (species richness) estimators that have been applied to T-cell repertoires and the methods used to validate these estimators. We show that existing approaches have significant shortcomings, and frequently underestimate true TCR diversity. We highlight our recently developed estimator, DivE, which can accurately estimate diversity across a range of immunological and biological systems.

Journal article

Ahmed R, Westera L, Elemans M, Drylewicz J, Zhang Y, Tesselaar K, de Boer RJ, Baboonian C, Macallan DC, Borghans JA, Asquith Bet al., 2014, Resolving estimates of in vivo lymphocyte turnover from deuterated-glucose and heavy water in a murine model, IMMUNOLOGY, Vol: 143, Pages: 62-62, ISSN: 0019-2805

Journal article

Boelen L, O'Neill PK, Boyton R, Altmann D, Asquith Bet al., 2014, Mapping MHC-II epitopes from Elispot data, the Bayesian way, IMMUNOLOGY, Vol: 143, Pages: 185-186, ISSN: 0019-2805

Journal article

Niederer HA, Laydon DJ, Melamed A, Elemans M, Asquith B, Matsuoka M, Bangham CRMet al., 2014, HTLV-1 proviral integration sites differ between asymptomatic carriers and patients with HAM/TSP, Virology Journal, Vol: 11, ISSN: 1743-422X

Background: HTLV-1 causes proliferation of clonal populations of infected T cells in vivo, each clone defined by aunique proviral integration site in the host genome. The proviral load is strongly correlated with odds of theinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is evidence thatasymptomatic HTLV-1 carriers (ACs) have a more effective CD8 + T cell response, including a higher frequency ofHLA class I alleles able to present peptides from a regulatory protein of HTLV-1, HBZ. We have previously shownthat specific features of the host genome flanking the proviral integration site favour clone survival and spontaneousexpression of the viral transactivator protein Tax in naturally infected PBMCs ex vivo. However, the previous studies werenot designed or powered to detect differences in integration site characteristics between ACs and HAM/TSP patients.Here, we tested the hypothesis that the genomic environment of the provirus differs systematically between ACs andHAM/TSP patients, and between individuals with strong or weak HBZ presentation.Methods: We used our recently described high-throughput protocol to map and quantify integration sites in 95 HAM/TSP patients and 68 ACs from Kagoshima, Japan, and 75 ACs from Kumamoto, Japan. Individuals with 2 or more HLAclass I alleles predicted to bind HBZ peptides were classified ‘strong’ HBZ binders; the remainder were classified ‘weakbinders’.Results: The abundance of HTLV-1-infected T cell clones in vivo was correlated with proviral integration in genes andin areas with epigenetic marks associated with active regulatory elements. In clones of equivalent abundance, integrationsites in genes and active regions were significantly more frequent in ACs than patients with HAM/TSP, irrespectiveof HBZ binding and proviral load. Integration sites in genes were also more frequent in strong HBZ binders than weakHBZ binders.Conclusion: Clonal abundance is correl

Journal article

Laydon DJ, Melamed A, Sim A, Gillet NA, Sim K, Darko S, Kroll JS, Douek DC, Price DA, Bangham CRM, Asquith Bet al., 2014, Quantification of HTLV-1 Clonality and TCR Diversity, PLOS COMPUTATIONAL BIOLOGY, Vol: 10

Journal article

Elemans M, Florins A, Willems L, Asquith Bet al., 2014, Rates of CTL Killing in Persistent Viral Infection In Vivo, PLOS COMPUTATIONAL BIOLOGY, Vol: 10, ISSN: 1553-734X

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.

Journal article

Seich al Basatena NK, Chatzimichalis K, Graw F, Frost SDW, Regoes RR, Asquith Bet al., 2013, Can Non-Lytic CD8+ T cells Drive HIV-1 Escape, PLOS Pathogens, Vol: 11

Journal article

Westera L, Drylewicz J, den Braber I, Mugwagwa T, van der Maas I, Kwast L, Volman T, van de Weg-Schrijver EHR, Bartha I, Spierenburg G, Gaiser K, Ackermans MT, Asquith B, de Boer RJ, Tesselaar K, Borghans JAMet al., 2013, Closing the gap between T-cell life span estimates from stable isotope-labeling studies in mice and humans, BLOOD, Vol: 122, Pages: 2205-2212, ISSN: 0006-4971

Journal article

Bangham C, Cook L, Laydon D, Asquith B, Melamed Aet al., 2013, Clonality, latency and integration of HTLV-1 in vivo, RETROVIROLOGY, Vol: 10, Pages: S3-S3, ISSN: 1742-4690

Journal article

Bangham C, Cook L, Laydon D, Asquith B, Melamed Aet al., 2013, Clonality, latency and integration of HTLV-1 in vivo, Retrovirology, Vol: 10

Journal article

Gillet NA, Cook L, Laydon DJ, Hlela C, Verdonck K, Alvarez C, Gotuzzo E, Clark D, Farre L, Bittencourt A, Asquith B, Taylor GP, Bangham CRMet al., 2013, Strongyloidiasis and Infective Dermatitis Alter Human T Lymphotropic Virus-1 Clonality in vivo, PLOS PATHOGENS, Vol: 9, ISSN: 1553-7374

Journal article

Cook LB, Elemans M, Rowan AG, Asquith Bet al., 2013, HTLV-1: Persistence and pathogenesis, VIROLOGY, Vol: 435, Pages: 131-140, ISSN: 0042-6822

Journal article

O'Connor GM, Al Basatena N-KS, Olavarria V, MacNamara A, Vine A, Ying Q, Hisada M, Galvao-Castro B, Asquith B, McVicar DWet al., 2012, In contrast to HIV, KIR3DS1 does not influence outcome in HTLV-1 retroviral infection, HUMAN IMMUNOLOGY, Vol: 73, Pages: 783-787, ISSN: 0198-8859

Journal article

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