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Cook LBM, Melamed A, Demontis MA, et al., 2016, Rapid dissemination of human T-lymphotropic virus type 1 during primary infection in transplant recipients, Retrovirology, Vol: 13, ISSN: 1742-4690
BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) infects an estimated 10 million persons globally with transmission resulting in lifelong infection. Disease, linked to high proviral load, occurs in a minority. In established infection HTLV-1 replicates through infectious spread and clonal expansion of infected lymphocytes. Little is known about acute HTLV-1 infection. The kinetics of early HTLV-1 infection, following transplantation-acquired infection in three recipients from one HTLV-1 infected donor, is reported. The recipients were treated with two HTLV-1 enzyme inhibitors 3 weeks post exposure following the detection of HTLV-1 provirus at low level in each recipient. HTLV-1 infection was serially monitored by serology, quantification of proviral load and HTLV-1 2LTR DNA circles and by HTLV-1 unique integration site analysis.ResultsHTLV-1 antibodies were first detected 16–39 days post-transplantation. HTLV-1 provirus was detected by PCR on day 16–23 and increased by 2–3 log by day 38–45 with a peak proviral doubling time of 1.4 days, after which steady state was reached. The rapid proviral load expansion was associated with high frequency of HTLV-1 2LTR DNA circles. The number of HTLV-1 unique integration sites was high compared with established HTLV-1 infection. Clonal expansion of infected cells was detected as early as day 37 with high initial oligoclonality index, consistent with early mitotic proliferation.ConclusionsIn recipients infected through organ transplantation HTLV-1 disseminated rapidly despite early anti-HTLV-1 treatment. Proviral load set point was reached within 6 weeks. Seroconversion was not delayed. Unique integration site analysis and HTLV-1 2LTR DNA circles indicated early clonal expansion and high rate of infectious spread.
Rowan AG, Bangham CRM, 2016, The pathogenesis of HTLV-1-associated myelopathy/tropical spastic paraparesis, Neurotropic Viral Infections: Volume 2: Neurotropic Retroviruses, DNA Viruses, Immunity and Transmission, Pages: 3-20, ISBN: 9783319331881
Human T lymphotropic virus 1 (HTLV-1) was discovered in 1980, when Robert Gallo and his colleagues observed production of retroviral particles by a cell line established from a patient with a T-cell lymphoma (Poiesz et al. 1980). Concurrently, two groups in Jamaica and Japan detected HTLV-1-specific antibodies in the cerebrospinal fluid (CSF) and serum of patients with a progressive myelopathy that was previously known as tropical spastic paraparesis (TSP) and named by the Japanese group HTLV-1-associated myelopathy (HAM) (Gessain et al. 1985; Osame et al. 1986). TSP and HAM were subsequently identified as the same condition, and the disease is now designated HAM/TSP. HAM/TSP is characterised by lesions in the spinal cord, resulting in a loss of control of motor functions below the waist, constipation, incontinence and neuropathic pain. The primary target cell infected by HTLV-1 in vivo is the CD4+ T lymphocyte: HTLV-1 is not neurotropic in the strict sense, because it does not infect neurons. Instead, HTLV-1 reaches the CNS via migration of infected lymphocytes across the blood-brain barrier (BBB), and this process is thought to initiate HAM/TSP. The risk of developing HAM/TSP rises exponentially with increasing viral burden (Nagai et al. 1998), and whilst the disease is not directly life-threatening, it lowers life expectancy and causes significant morbidity (Olindo et al. 2006). Here, we discuss the recent developments in our understanding of the factors influencing HTLV-1 spread, immune control and the pathogenesis of the inflammatory disease.
Kirk PDW, Huvet M, Melamed A, et al., 2015, Retroviruses integrate into a shared, non-palindromic motif
<jats:p>Palindromic consensus nucleotide sequences are found at the genomic integration sites of retroviruses and other transposable elements. It has been suggested that the palindromic consensus arises as a consequence of structural symmetry in the integrase complex, but the precise mechanism has yet to be elucidated. Here we perform a statistical analysis of large datasets of HTLV-1 and HIV-1 integration sites. The results show that the palindromic consensus sequence is not present in individual integration sites, but appears to arise in the population average as a consequence of the existence of a non-palindromic nucleotide motif that occurs in approximately equal proportions on the plus-strand and the minus-strand of the host genome. We demonstrate that palindromic probability position matrices are characteristic of such situations. We develop a generally applicable algorithm to sort the individual integration site sequences into plus-strand and minus-strand subpopulations. We apply this algorithm to identify the respective integration site nucleotide motifs of five retroviruses of different genera: HTLV-1, HIV-1, MLV, ASLV, and PFV}. The results reveal a non-palindromic motif that is shared between these retroviruses.</jats:p>
Rockwood N, Cook L, Kagdi H, et al., 2015, Immune compromise in HIV-1/HTLV-1 coinfection with paradoxical resolution of CD4 lymphocytosis during antiretroviral therapy: a case report, Medicine, Vol: 94, ISSN: 0304-5412
Abstract: Human immunodeficiency virus type-1 (HIV-1) and human T lymphotropic virus type-1 (HTLV-1) infections have complex effects on adaptive immunity, with specific tropism for, but contrasting effects on, CD4 T lymphocytes: depletion with HIV-1, proliferation with HTLV-1. Impaired T lymphocyte function occurs early in HIV-1 infection but opportunistic infections (OIs) rarely occur in the absence of CD4 lymphopenia. In the unusual case where a HIV-1 infected individual with a high CD4 count presents with recurrent OIs, a clinician is faced with the possibility of a second underlying comorbidity.We present a case of pseudo-adult T cell leukemia/lymphoma (ATLL) in HIV-1/HTLV-1 coinfection where the individual fulfilled Shimoyama criteria for chronic ATLL and had pulmonary Mycobacterium kansasii, despite a high CD4 lymphocyte count. However, there was no evidence of clonal T-cell proliferation by T-cell receptor gene rearrangement studies nor of monoclonal HTLV-1 integration by high-throughput sequencing. Mutually beneficial interplay between HIV-1 and HTLV-1, maintaining high level HIV-1 and HTLV-1 viremia and proliferation of poorly functional CD4 cells despite chronicity of infection is a postulated mechanism.Despite good microbiological response to antimycobacterial therapy, the patient remained systemically unwell with refractory anemia. Subsequent initiation of combined antiretroviral therapy led to paradoxical resolution of CD4 T lymphocytosis as well as HIV-1 viral suppression and decreased HTLV-1 proviral load. This is proposed to be the result of attenuation of immune activation post-HIV virological control.This case illustrates the importance of screening for HTLV-1 in HIV-1 patients with appropriate clinical presentation and epidemiological risk factors and explores mechanisms for the complex interactions on HIV-1/HTLV-1 adaptive immunity.
Bangham CRM, Melamed A, Laydon D, et al., 2015, HTLV-1 drives vigorous clonal expansion of infected CD8 + T cells in natural infection, Retrovirology, Vol: 12, ISSN: 1742-4690
BackgroundHuman T-lymphotropic Virus Type I (HTLV-1) is a retrovirus that persistently infects 5–10 million individuals worldwide and causes disabling or fatal inflammatory and malignant diseases. The majority of the HTLV-1 proviral load is found in CD4 + T cells, and the phenotype of adult T cell leukemia (ATL) is typically CD4 + . HTLV-1 also infects CD8 + cells in vivo, but the relative abundance and clonal composition of the two infected subpopulations have not been studied. We used a high-throughput DNA sequencing protocol to map and quantify HTLV-1 proviral integration sites in separated populations of CD4 + cells, CD8 + cells and unsorted peripheral blood mononuclear cells from 12 HTLV-1-infected individuals.ResultsWe show that the infected CD8 + cells constitute a median of 5 % of the HTLV-1 proviral load. However, HTLV-1-infected CD8 + clones undergo much greater oligoclonal proliferation than the infected CD4 + clones in infected individuals, regardless of disease manifestation. The CD8 + clones are over-represented among the most abundant clones in the blood and are redetected even after several years.ConclusionsWe conclude that although they make up only 5 % of the proviral load, the HTLV-1-infected CD8 + T-cells make a major impact on the clonal composition of HTLV-1-infected cells in the blood. The greater degree of oligoclonal expansion observed in the infected CD8 + T cells, contrasts with the CD4 + phenotype of ATL; cases of CD8 + adult T-cell leukaemia/lymphoma are rare. This work is consistent with growing evidence that oligoclonal expansion of HTLV-1-infected cells is not sufficient for malignant transformation.
Bangham CRM, Ratner L, 2015, How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)?, Current Opinion in Virology, Vol: 14, Pages: 93-100, ISSN: 1879-6265
Turpin J, Alais S, Marcais A, et al., 2015, Treatment of an aggressive STLV-1 associated lymphoma in a naturally infected baboon, 17th International Conference on Human Retroviruses: HTLV and Related Viruses, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
Kagdi H, Rowan A, Child F, et al., 2015, CD8 malignant proliferation in association with human T cell lymphotropic Virus 1 infection: a case report, 17th International Conference on Human Retroviruses: HTLV and Related Viruses, Publisher: BioMed Central, Pages: P68-P68, ISSN: 1742-4690
Kagdi H, Rowan A, Demontis MA, et al., 2015, Molecular characterization of heterogeneity in adult T-cell leukaemia/lymphoma, Publisher: BioMed Central, ISSN: 1742-4690
Kagdi H, Rowan A, Demontis MA, et al., 2015, Molecular characterization of heterogeneity in adult T-cell leukaemia/lymphoma, RETROVIROLOGY, Vol: 12, ISSN: 1742-4690
Bangham CRM, Araujo A, Yamano Y, et al., 2015, HTLV-1-associated myelopathy/tropical spastic paraparesis., Nature Reviews Disease Primers, Vol: 1, ISSN: 2056-676X
Human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive disease of the CNS that causes weakness or paralysis of the legs, lower back pain and urinary symptoms. HAM/TSP was first described in Jamaica in the nineteenth century, but the aetiology of the condition, infection with the retrovirus HTLV-1, was only identified in the 1980s. HAM/TSP causes chronic disability and, accordingly, imposes a substantial health burden in areas where HTLV-1 infection is endemic. Since the discovery of the cause of HAM/TSP, considerable advances have been made in the understanding of the virology, immunology, cell biology and pathology of HTLV-1 infection and its associated diseases. However, progress has been limited by the lack of accurate animal models of the disease. Moreover, the treatment of HAM/TSP remains highly unsatisfactory: antiretroviral drugs have little impact on the infection and, although potential disease-modifying therapies are widely used, their value is unproved. At present, clinical management is focused on symptomatic treatment and counselling. Here, we summarize current knowledge on the epidemiology, pathogenesis and treatment of HAM/TSP and identify areas in which further research is needed.
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.
Bangham CRM, Araujo A, Yamano Y, et al., 2015, HTLV-1-associated myelopathy/tropical spastic paraparesis, NATURE REVIEWS DISEASE PRIMERS, Vol: 1, ISSN: 2056-676X
Rowan AG, Suemori K, Fujiwara H, et al., 2014, Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression, Retrovirology, Vol: 11, ISSN: 1742-4690
BackgroundImmunogenetic evidence indicates that cytotoxic T lymphocytes (CTLs) specific for the weak CTL antigen HBZ limit HTLV-1 proviral load in vivo, whereas there is no clear relationship between the proviral load and the frequency of CTLs specific for the immunodominant antigen Tax. In vivo, circulating HTLV-1-infected cells express HBZ mRNA in contrast, Tax expression is typically low or undetectable. To elucidate the virus-suppressing potential of CTLs targeting HBZ, we compared the ability of HBZ- and Tax-specific CTLs to lyse naturally-infected cells, by co-incubating HBZ- and Tax-specific CTL clones with primary CD4+ T cells from HLA-matched HTLV-1-infected donors. We quantified lysis of infected cells, and tested whether specific virus-induced host cell surface molecules determine the susceptibility of infected cells to CTL-mediated lysis.ResultsPrimary infected cells upregulated HLA-A*02, ICAM-1, Fas and TRAIL-R1/2 in concert with Tax expression, forming efficient targets for both HTLV-1-specific CTLs and CTLs specific for an unrelated virus. We detected expression of HBZ mRNA (spliced isoform) in both Tax-expressing and non-expressing infected cells, and the HBZ26–34 epitope was processed and presented by cells transfected with an HBZ expression plasmid. However, when coincubated with primary cells, a high-avidity HBZ-specific CTL clone killed significantly fewer infected cells than were killed by a Tax-specific CTL clone. Finally, incubation with Tax- or HBZ-specific CTLs resulted in a significant decrease in the frequency of cells expressing high levels of HLA-A*02.ConclusionsHTLV-1 gene expression in primary CD4+ T cells non-specifically increases susceptibility to CTL lysis. Despite the presence of HBZ spliced-isoform mRNA, HBZ epitope presentation by primary cells is significantly less efficient than that of Tax.Keywords: HTLV-1; Retrovirus; Cytotoxic lymphocyte response; CTL; HBZ; Tax; HLA; ICAM-1; Fas
Rowan AG, Suemori K, Fujiwara H, et al., 2014, Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression, Retrovirology, Vol: 11
Niederer HA, Bangham CRM, 2014, Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy, Viruses, Vol: 6, Pages: 4140-4164, ISSN: 1999-4915
Retroviral vectors have been successfully used therapeutically to restoreexpression of genes in a range of single-gene diseases, including several primaryimmunodeficiency disorders. Although clinical trials have shown remarkable results, therehave also been a number of severe adverse events involving malignant outgrowth of atransformed clonal population. This clonal expansion is influenced by the integration siteprofile of the viral integrase, the transgene expressed, and the effect of the viral promoterson the neighbouring host genome. Infection with the pathogenic human retrovirus HTLV-1also causes clonal expansion of cells containing an integrated HTLV-1 provirus. Althoughthe majority of HTLV-1-infected people remain asymptomatic, up to 5% develop anaggressive T cell malignancy. In this review we discuss recent findings on the role of thegenomic integration site in determining the clonality and the potential for malignanttransformation of cells carrying integrated HTLV-1 or gene therapy vectors, and how theseresults have contributed to the understanding of HTLV-1 pathogenesis and to improvementsin gene therapy vector safety.
Niederer HA, Laydon DJ, Melamed A, et 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
Chataway J, Schuerer N, Alsanousi A, et al., 2014, Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial, LANCET, Vol: 383, Pages: 2213-2221, ISSN: 0140-6736
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- Citations: 269
Cook LB, Melamed A, Niederer H, et al., 2014, The role of HTLV-1 clonality, proviral structure, and genomic integration site in adult T-cell leukemia/lymphoma, Blood, Vol: 123, Pages: 3925-3931, ISSN: 0006-4971
Adult T-cell leukemia/lymphoma (ATL) occurs in ∼5% of human T-lymphotropic virus type 1 (HTLV-1)–infected individuals and is conventionally thought to be a monoclonal disease in which a single HTLV-1+ T-cell clone progressively outcompetes others and undergoes malignant transformation. Here, using a sensitive high-throughput method, we quantified clonality in 197 ATL cases, identified genomic characteristics of the proviral integration sites in malignant and nonmalignant clones, and investigated the proviral features (genomic structure and 5′ long terminal repeat methylation) that determine its capacity to express the HTLV-1 oncoprotein Tax. Of the dominant, presumed malignant clones, 91% contained a single provirus. The genomic characteristics of the integration sites in the ATL clones resembled those of the frequent low-abundance clones (present in both ATL cases and carriers) and not those of the intermediate-abundance clones observed in 24% of ATL cases, suggesting that oligoclonal proliferation per se does not cause malignant transformation. Gene ontology analysis revealed an association in 6% of cases between ATL and integration near host genes in 3 functional categories, including genes previously implicated in hematologic malignancies. In all cases of HTLV-1 infection, regardless of ATL, there was evidence of preferential survival of the provirus in vivo in acrocentric chromosomes (13, 14, 15, 21, and 22).
Bangham CRM, Cook LB, Melamed A, 2014, HTLV-1 clonality in adult T-cell leukaemia and non-malignant HTLV-1 infection, Seminars in Cancer Biology, Vol: 26, Pages: 89-98, ISSN: 1044-579X
Human T lymphotropic virus type 1 (HTLV-1) causes a range of chronic inflammatory diseases and an aggressive malignancy of T lymphocytes known as adult T-cell leukaemia/lymphoma (ATLL). A cardinal feature of HTLV-1 infection is the presence of expanded clones of HTLV-1-infected T cells, which may persist for decades. A high viral burden (proviral load) is associated with both the inflammatory and malignant diseases caused by HTLV-1, and it has been believed that the oligoclonal expansion of infected cells predisposes to these diseases. However, it is not understood what regulates the clonality of HTLV-1 in vivo, that is, the number and abundance of HTLV-1-infected T cell clones. We review recent advances in the understanding of HTLV-1 infection and disease that have come from high-throughput quantification and analysis of HTLV-1 clonality in natural infection.
Laydon DJ, Melamed A, Sim A, et al., 2014, Quantification of HTLV-1 Clonality and TCR Diversity, PLOS COMPUTATIONAL BIOLOGY, Vol: 10
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- Citations: 53
Melamed A, Witkover AD, Laydon DJ, et al., 2014, Clonality of HTLV-2 in natural infection, PLoS Pathogens, Vol: 10, Pages: 1-9, ISSN: 1553-7366
Human T-lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) both cause lifelong persistent infections, but differ in their clinical outcomes. HTLV-1 infection causes a chronic or acute T-lymphocytic malignancy in up to 5% of infected individuals whereas HTLV-2 has not been unequivocally linked to a T-cell malignancy. Virus-driven clonal proliferation of infected cells both in vitro and in vivo has been demonstrated in HTLV-1 infection. However, T-cell clonality in HTLV-2 infection has not been rigorously characterized. In this study we used a high-throughput approach in conjunction with flow cytometric sorting to identify and quantify HTLV-2-infected T-cell clones in 28 individuals with natural infection. We show that while genome-wide integration site preferences in vivo were similar to those found in HTLV-1 infection, expansion of HTLV-2-infected clones did not demonstrate the same significant association with the genomic environment of the integrated provirus. The proviral load in HTLV-2 is almost confined to CD8+ T-cells and is composed of a small number of often highly expanded clones. The HTLV-2 load correlated significantly with the degree of dispersion of the clone frequency distribution, which was highly stable over ∼8 years. These results suggest that there are significant differences in the selection forces that control the clonal expansion of virus-infected cells in HTLV-1 and HTLV-2 infection. In addition, our data demonstrate that strong virus-driven proliferation per se does not predispose to malignant transformation in oncoretroviral infections.
Rowan AG, McCallin A, Niederer HA, et al., 2014, HTLV-1 gene expression by individual infected clones determines susceptibility to lysis by cytotoxic T lymphocytes specific for Tax and HBZ, Retrovirology, Vol: 11
Marçais A, Hanssens K, Cook L, et al., 2014, Recurrent TET2 mutations in adult T cell leukemia, Retrovirology, Vol: 11
Kagdi H, Melamed A, Hilburn S, et al., 2014, The potential of CD127 as a prognostic and residual disease marker in chronic adult T cell leukaemia/lymphoma, Retrovirology, Vol: 11
Kirk P, Witkover A, Bangham CRM, et al., 2013, Balancing the Robustness and Predictive Performance of Biomarkers, JOURNAL OF COMPUTATIONAL BIOLOGY, Vol: 20, Pages: 979-989, ISSN: 1066-5277
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Bangham C, Cook L, Laydon D, et al., 2013, Clonality, latency and integration of HTLV-1 in vivo, RETROVIROLOGY, Vol: 10, Pages: S3-S3, ISSN: 1742-4690
Bangham C, Cook L, Laydon D, et al., 2013, Clonality, latency and integration of HTLV-1 in vivo, Retrovirology, Vol: 10
Kagdi H, Hilburn S, Rowan A, et al., 2013, THE POTENTIAL OF CD127 AS A PROGNOSTIC AND RESIDUAL DISEASE MARKER IN CHRONIC ADULT T CELL LEUKEMIA/LYMPHOMA., Publisher: FERRATA STORTI FOUNDATION, Pages: 139-140, ISSN: 0390-6078
Gillet NA, Cook L, Laydon DJ, et al., 2013, Strongyloidiasis and Infective Dermatitis Alter Human T Lymphotropic Virus-1 Clonality <i>in vivo</i>, PLOS PATHOGENS, Vol: 9, ISSN: 1553-7374
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- Citations: 52
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