Publications
72 results found
Cook LB, Rowan AG, Demontis MA, et al., 2016, HTLV-1 proviral load after two months' treatment with anti-CCR4 monoclonal antibody mogamulizumab predicts a molecular response to disease and durable clinical remission in leukaemic subtypes of adult T-cell leukaemia/lymphoma, 58th Annual Meeting and Exposition of the American-Society-of-Hematology, Publisher: American Society of Hematology, Pages: 5356-5356, ISSN: 0006-4971
Rowan AG, Witkover A, Melamed A, et al., 2016, T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells., PLoS Pathog, Vol: 12
There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease.
Manivannan K, Rowan AG, Tanaka Y, et al., 2016, CADM1/TSLC1 Identifies HTLV-1-Infected Cells and Determines Their Susceptibility to CTL-Mediated Lysis., PLoS Pathog, Vol: 12
Human T cell lymphotropic virus-1 (HTLV-1) primarily infects CD4+ T cells, causing inflammatory disorders or a T cell malignancy in 5% to 10% of carriers. The cytotoxic T lymphocyte (CTL) response is a key factor that controls the viral load and thus the risk of disease. The ability to detect the viral protein Tax in primary cells has made it possible to estimate the rate at which Tax-expressing infected cells are eliminated by CTLs in persistently infected people. However, most HTLV-1-infected cells are Tax-at a given time, and their immunophenotype is poorly defined. Here, we aimed to identify a cell-surface molecule expressed by both Tax+ and Tax-HTLV-1-infected cells and use it to analyse the CTL response in fresh peripheral blood mononuclear cells. Cell adhesion molecule 1 (CADM1/TSLC1) was the best single marker of HTLV-1 infection, identifying HTLV-1-infected cells with greater sensitivity and specificity than CD25, CCR4 or ICAM-1. CADM1+CD4+ T cells carried a median of 65% of proviral copies in peripheral blood. In a cohort of 23 individuals, we quantified the rate of CTL-mediated killing of Tax+ and Tax-CADM1+ cells. We show that CADM1 expression is associated with enhanced susceptibility of infected cells to CTL lysis: despite the immunodominance of Tax in the CTL response, Tax+CADM1- cells were inefficiently lysed by CTLs. Upregulation of the CADM1 ligand CRTAM on CD8+ T cells correlated with efficient lysis of infected cells. Tax-CADM1+ cells were lysed at a very low rate by autologous CTLs, however, were efficiently killed when loaded with exogenous peptide antigen. High expression of CADM1 on most HTLV-1-infected cells in the face of enhanced CTL counterselection implies that CADM1 confers a strong benefit on the virus.
Satou Y, Miyazato P, Ishihara Y, et al., 2016, The retrovirus HTLV-1 inserts an ectopic CTCF-binding site into the human genome, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: 3054-3059, ISSN: 0027-8424
Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus thatcauses malignant and inflammatory diseases in 10% of infectedpeople. A typical host has between 104and 105clones of HTLV-1-infected T lymphocytes, each clone distinguished by the genomicintegration site of the single-copy HTLV-1 provirus. TheHBZgeneis constitutively expressed from the minus strand of the provirus,whereas plus-strand expression, required for viral propagation touninfected cells, is suppressed or intermittentin vivo, allowingescape from host immune surveillance. It remains unknown whatregulates this pattern of proviral transcription and latency. Herewe show that CTCF, a key regulator of chromatin structure andfunction, binds to the provirus at a sharp border in epigeneticmodifications in the pX region of the HTLV-1 provirus, in T cellsnaturally infected with HTLV-1. CTCF is a zinc-finger protein thatbinds to an insulator region in genomic DNA and plays a funda-mental role in controlling higher-order chromatin structure andgene expression in vertebrate cells. We show that CTCF boundto HTLV-1 acts as an enhancer blocker, regulates HTLV-1 mRNAsplicing, and forms long-distance interactions with flanking hostchromatin. CTCF binding sites have been propagated through-out the genome by transposons in certain primate lineages, butCTCF binding has not previously been described in present-dayexogenous retroviruses. The presence of an ectopic CTCF bindingsite introduced by the retrovirus in tens of thousands of genomiclocations has the potential to cause widespread abnormalities inhost cell chromatin structure and gene expression.
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.
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.
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, 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
Rowan AG, Fields P, Taylor GP, et al., 2015, T-cell receptor chain Vbeta subunit staining to quantify the malignant clone in adult T-cell leukemia, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
Satou Y, Paola M, Ishihara K, et al., 2015, HTLV-1 inserts an ectopic CTCF-binding site into the human genome, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
- Author Web Link
- Cite
- Citations: 1
Melamed A, Yaguchi H, Rowan A, et al., 2015, Comparative analysis of gene expression patterns in the HTLV-1 infected T-cell clones, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
Yaguchi H, Melamed A, Rowan A, et al., 2015, Identification of long-range chromatin interactions between HTLV-1 and the host genome, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
Manivannan K, Rowan AG, Taylor GP, et al., 2015, Tumor suppressor in lung cancer identifies latency infected cells in non malignant HTLV-1 infection, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
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
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.
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
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
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
Twigger K, Rowan A, Seich al Basatena N-K, et al., 2014, Frequency and function of KIR+ CD8+ T cells in HTLV-1 infection, Retrovirology, Vol: 11
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
Cook LB, Elemans M, Rowan AG, et al., 2013, HTLV-1: Persistence and pathogenesis, VIROLOGY, Vol: 435, Pages: 131-140, ISSN: 0042-6822
- Author Web Link
- Cite
- Citations: 72
Cook LB, Rowan AG, Melamed A, et al., 2012, HTLV-1-infected T cells contain a single integrated provirus in natural infection, BLOOD, Vol: 120, Pages: 3488-3490, ISSN: 0006-4971
- Author Web Link
- Cite
- Citations: 79
Rowan AG, Asquith B, Taylor GP, et al., 2011, Susceptibility of HBZ and Tax expressing primary HTLV-1+ T cell clones to CTL lysis, Retrovirology, Vol: 8
Kress AK, Kalmer M, Rowan AG, et al., 2011, The tumour marker Fascin is strongly induced by Tax of HTLV-1 through NF-κB signals in T lymphocytes, Retrovirology, Vol: 8
M Bangham CR, Gillet N, Melamed A, et al., 2011, HTLV-1 persistence in vivo: clonality, dynamics and immune response, Retrovirology, Vol: 8
Fox JM, Hiburn S, Cook LBM, et al., 2011, Circularised 1 and 2 LTR DNA circles are present in freshly- and chronically-infected cell lines and patient PBMCs, indicating ongoing reverse transcriptase usage, Retrovirology, Vol: 8
Rowan AG, Bangham CRM, 2011, Is there a role for HTLV-1-specific CTL in adult T-cell Leukemia/Lymphoma?, Leukemia Research and Treatment, Vol: 2012, ISSN: 2090-3219
ATLL is an aggressive malignancy of T cells that affects about 5% of individuals infected with HTLV-1. The precise mechanism of oncogenesis is not known, but there is evidence that two regulatory viral proteins, Tax and HBZ, are involved. A high set point proviral load is associated with development of ATLL or a chronic inflammatory condition, HAM/TSP. Several lines of evidence, including HLA class 1 association studies and in vitro killing assays, indicate that cytotoxic T lymphocytes are instrumental in determining this proviral load set point. Prior studies have focused chiefly on the CTL response to the immunodominant Tax protein: efficient lysis of Tax-expressing cells inversely correlates with proviral load in nonmalignant infection. However, a recent study showed that strong binding of peptides from HBZ, but not Tax, to HLA class 1 molecules was associated with a low proviral load and a reduced risk of developing HAM/TSP, indicating an important role for HBZ-specific CTL in determining infection outcome. In comparison with nonmalignant infection, HTLV-1-specific CTLs in ATLL patients are reduced in frequency and functionally deficient. Here we discuss the nature of protective CTL responses in nonmalignant HTLV-1 infection and explore the potential of CTLs to protect against ATLL.
Kress AK, Kalmer M, Rowan AG, et al., 2011, The tumor marker Fascin is strongly induced by the Tax oncoprotein of HTLV-1 through NF-κB signals, BLOOD, Vol: 117, Pages: 3609-3612, ISSN: 0006-4971
- Author Web Link
- Cite
- Citations: 28
Hilburn S, Rowan A, Demontis M-A, et al., 2011, In vivo Expression of Human T-lymphotropic Virus Type 1 Basic Leucine-Zipper Protein Generates Specific CD8+and CD4+T-Lymphocyte Responses that Correlate with Clinical Outcome, JOURNAL OF INFECTIOUS DISEASES, Vol: 203, Pages: 529-536, ISSN: 0022-1899
- Author Web Link
- Open Access Link
- Cite
- Citations: 53
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.