Imperial College London

DrAileenRowan

Faculty of MedicineDepartment of Immunology and Inflammation

Research Associate
 
 
 
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Contact

 

+44 (0)20 7594 3908a.rowan

 
 
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Location

 

455Wright Fleming WingSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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60 results found

Rowan AG, May P, Badhan A, Herrera C, Watber P, Penn R, Crone MA, Storch M, Garson JA, McClure M, Freemont PS, Madona P, Randell P, Taylor GPet al., 2021, Optimized protocol for a quantitative SARS-CoV-2 duplex RT-qPCR assay with internal human sample sufficiency control., Journal of Virological Methods, Vol: 294, Pages: 1-7, ISSN: 0166-0934

There is growing evidence that measurement of SARS-CoV-2 viral copy number can inform clinical and public health management of SARS-CoV-2 carriers and COVID-19 patients. Here we show that quantification of SARS-CoV-2 is feasible in a clinical setting, using a duplex RT-qPCR assay which targets both the E gene (Charité assay) and a human RNA transcript, RNase P (CDC assay) as an internal sample sufficiency control. Samples in which RNase P is not amplified indicate that sample degradation has occurred, PCR inhibitors are present, RNA extraction has failed or swabbing technique was insufficient. This important internal control reveals that 2.4% of nasopharyngeal swabs (15/618 samples) are inadequate for SARS-CoV-2 testing which, if not identified, could result in false negative results. We show that our assay is linear across at least 7 logs and is highly reproducible, enabling the conversion of Cq values to viral copy numbers using a standard curve. Furthermore, the SARS-CoV-2 copy number was independent of the RNase P copy number indicating that the per-swab viral copy number is not dependent on sampling- further allowing comparisons between samples. The ability to quantify SARS-CoV-2 viral copy number will provide an important opportunity for viral burden-guided public health and clinical decision making.

Journal article

Rosadas de Oliveira C, Woo T, Haddow J, Rowan A, Taylor Get al., 2021, Anti-HTLV-1/2 IgG antibodies in the breastmilk of seropositive mothers, Microorganisms, Vol: 9, Pages: 1-8, ISSN: 2076-2607

Background: HTLV-1/2 mother-to-child transmission (MTCT) is an important route for the maintenance of HTLV-1/2 within populations and disproportionally contributes to the burden of HTLV-1-associated diseases. Avoidance of breastfeeding is the safest recommendation to prevent MTCT. Due to the benefits of breastfeeding, alternative methods that would allow seropositive mothers to breastfeed their babies are needed. There is limited knowledge about HTLV-1/2 infection and breastmilk. Methods: Paired blood and milk samples collected from HTLV-1/2 seropositive mothers were tested for HTLV-1 proviral load (PVL) quantification and for the detection of anti-HTLV-1/2 IgG. Results: All breastmilk samples had detectable anti-HTLV-1/2 IgG. HTLV-1/2 proviral DNA was detected in all samples except for one. HTLV-1 PVL and IgG binding ratio (BR) was similar in milk and plasma. However, antibody titer was significantly higher in blood (Median (95%CI): Milk:128 (32–512); Plasma:131,584 (16,000–131,584), p < 0.05). There was a strong correlation between HTLV-1 PVL, anti-HTLV-1/2 IgG BR, and titer when comparing milk and blood. PVL did not correlate with antibody BR nor titer in blood or milk. Conclusions: Anti-HTLV-1/2 IgG are present in milk in the same proportion as blood but in lower quantity. PVL in milk correlates with blood.

Journal article

Katsuya H, Cook LBM, Rowan AG, Melamed A, Turpin J, Ito J, Islam S, Miyazato P, Jek Yang Tan B, Matsuo M, Miyakawa T, Nakata H, Matsushita S, Taylor GP, Bangham CRM, Kimura S, Satou Yet al., 2021, Clonality of HIV-1 and HTLV-1 infected cells in naturally coinfected individuals., Journal of Infectious Diseases, ISSN: 0022-1899

BACKGROUND: Coinfection with HIV-1 and HTLV-1 diminishes the value of the CD4 + T-cell count in diagnosing AIDS, and increases the rate of HTLV-1-associated myelopathy. It remains elusive how HIV-1/HTLV-1 coinfection is related to such clinical characteristics. Here, we investigated the mutual effect of HIV-1/HTLV-1 coinfection on their integration sites (ISs) and the clonal expansion. METHODS: We extracted DNA from longitudinal peripheral blood samples from 7 HIV-1/HTLV-1 coinfected individuals, and from 12 HIV-1 and 13 HTLV-1 mono-infected individuals. The proviral loads (PVL) were quantified using real-time PCR. Viral ISs and clonality were quantified by ligation-mediated PCR followed by high-throughput sequencing. RESULTS: The PVL of both HIV-1 and HTLV-1 in coinfected individuals was significantly higher than that of the respective virus in mono-infected individuals. The degree of oligoclonality of both HIV-1- and HTLV-1-infected cells in co-infected individuals was also greater than that in mono-infected subjects. The ISs of HIV-1 in cases of coinfection were more frequently located in intergenic regions and transcriptionally silent regions, compared with HIV-1 mono-infected individuals. CONCLUSION: HIV-1/HTLV-1 coinfection makes an impact on the distribution of viral ISs and the clonality of virus-infected cells and thus may alter the risks of both HTLV-1- and HIV-1-associated disease.

Journal article

Wolf S, Haddow J, Greiller C, Taylor G, Cook L, Rowan Aet al., 2021, Quantification of T cell clonality in Human T cell leukaemia virus type-1 carriers can detect the development of Adult T cell Leukaemia early, Blood Cancer Journal, Vol: 11, Pages: 1-11, ISSN: 2044-5385

Adult T cell leukaemia/lymphoma (ATL) arises from clonally expanded T cells which are infected with Human T cell leukaemia virus type-1 (HTLV-1). Here, we show that ATL could be detected early in HTLV-1-carriers through quantification of T-cell receptor (TCR)Vβ subunit diversity on T-cells infected with HTLV-1 (CD3+CCR4+CD26-T-cells) using an ‘oligoclonality index’ (OCI-flow). We established a reference range for OCI-flow by analysing peripheral blood mononuclear cells (PBMCs) from HTLV-1-carriers who had not developed ATL in a median of 10.5 years follow up (n=38) and patients with ATL (n=30). In a third cohort of HTLV-1-carriers with no history or clinical evidence of ATL (n=106), 19% of high proviral load (PVL, ≥4 copies of HTLV-1/100 PBMCs) carriers had an OCI-flow in the ATL range, >0.770. Carriers with an OCI-flow >0.770 (n=14) had higher lymphocyte counts and PVLs, and were more likely to have a family history of ATL than carriers with OCI-flow ≤0.770. ATL subsequently developed in two of these 14 carriers but no carriers with OCI-flow ≤0.770 (p=0.03, cumulative follow-up 129 person-years). This method can be used to identify a subset of high-PVL HTLV-1-carriers at increased risk of developing ATL who may benefit from intervention therapy, prior to the detection of disease.

Journal article

Gibani MM, Toumazou C, Sohbati M, Sahoo R, Karvela M, Hon T-K, De Mateo S, Burdett A, Leung KYF, Barnett J, Orbeladze A, Luan S, Pournias S, Sun J, Flower B, Bedzo-Nutakor J, Amran M, Quinlan R, Skolimowska K, Herrera C, Rowan A, Badhan A, Klaber R, Davies G, Muir D, Randell P, Crook D, Taylor GP, Barclay W, Mughal N, Moore LSP, Jeffery K, Cooke GSet al., 2020, Assessing a novel, lab-free, point-of-care test for SARS-CoV-2 (CovidNudge): a diagnostic accuracy study., The Lancet Microbe, Vol: 1, Pages: e300-e307, ISSN: 2666-5247

Background: Access to rapid diagnosis is key to the control and management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Laboratory RT-PCR testing is the current standard of care but usually requires a centralised laboratory and significant infrastructure. We describe our diagnostic accuracy assessment of a novel, rapid point-of-care real time RT-PCR CovidNudge test, which requires no laboratory handling or sample pre-processing. Methods: Between April and May, 2020, we obtained two nasopharyngeal swab samples from individuals in three hospitals in London and Oxford (UK). Samples were collected from three groups: self-referred health-care workers with suspected COVID-19; patients attending emergency departments with suspected COVID-19; and hospital inpatient admissions with or without suspected COVID-19. For the CovidNudge test, nasopharyngeal swabs were inserted directly into a cartridge which contains all reagents and components required for RT-PCR reactions, including multiple technical replicates of seven SARS-CoV-2 gene targets (rdrp1, rdrp2, e-gene, n-gene, n1, n2 and n3) and human ribonuclease P (RNaseP) as sample adequacy control. Swab samples were tested in parallel using the CovidNudge platform, and with standard laboratory RT-PCR using swabs in viral transport medium for processing in a central laboratory. The primary analysis was to compare the sensitivity and specificity of the point-of-care CovidNudge test with laboratory-based testing. Findings: We obtained 386 paired samples: 280 (73%) from self-referred health-care workers, 15 (4%) from patients in the emergency department, and 91 (23%) hospital inpatient admissions. Of the 386 paired samples, 67 tested positive on the CovidNudge point-of-care platform and 71 with standard laboratory RT-PCR. The overall sensitivity of the point-of-care test compared with laboratory-based testing was 94% (95% CI 86-98) with an overall specificity of 100% (99-100). The sensitivity of the test varied

Journal article

Aanensen DM, Abudahab K, Adams A, Afifi S, Alam MT, Alderton A, Alikhan N-F, Allan J, Almsaud M, Alrezaihi A, Alruwaili M, Amato R, Andersson M, Angyal A, Aranday-Cortes E, Ariani C, Armstrong SD, Asamaphan P, Attwood S, Aydin A, Badhan A, Baker D, Baker P, Balcazar CE, Ball J, Barton AE, Bashton M, Baxter L, Beale M, Beaver C, Beckett A, Beer R, Beggs A, Bell A, Bellis KL, Bentley EG, Berriman M, Betteridge E, Bibby D, Bicknell K, Birchley A, Black G, Blane B, Bloomfield S, Bolt F, Bonsall DG, Bosworth A, Bourgeois Y, Boyd O, Bradshaw D, Breuer J, Bridgewater H, Brooks T, Broos A, Brown JR, Brown RL, Brunker K, Bucca G, Buck D, Bull M, Butcher E, Caddy SL, Caller LG, Cambell S, Carlile M, Carmichael S, Carrilero L, Castellano S, Chaloner J, Chand M, Chapman MR, Chappell J, Charles I, Chauhan AJ, Chawla A, Cheng E, Churcher CM, Clark G, Clark JJ, Collins J, Colquhoun R, Connor TR, Constantinidou C, Coombes J, Corden S, Cottrell S, Cowell A, Curran MD, Curran T, Dabrera G, Danesh J, Darby AC, de Cesare M, Martins LDO, de Silva TI, Debebe B, Dervisevic S, Dewar RA, Dia M, Dorman M, Dougan G, Dover L, Downing F, Drury E, du Plessis L, Dyal PL, Eccles R, Edwards S, Ellaby N, Elliott S, Eltringham G, Elumogo N, Essex S, Evans CM, Evans J, Nascimento FF, Fairley DJ, Farr B, Feltwell T, Ferguson N, Filipe ADS, Findlay J, Forrest LM, Forrest S, Foulser L, Francois S, Fraser C, Frost L, Gallagher E, Gallagher MD, Garcia-Dorival I, Gaskin A, Gatica-Wilcox B, Gavriil A, Geidelberg L, Gemmell M, Gerada A, Gifford L, Gilbert L, Gilmore P, Gilroy R, Girgis S, Glaysher S, Golubchik T, Goncalves S, Goodfellow I, Goodwin S, Graham C, Graham L, Grammatopoulos D, Green A, Green LR, Greenaway J, Gregory R, Groves DC, Groves N, Guest M, Gunson R, Haldenby S, Hall G, Hamilton WL, Han X, Harris KA, Harrison EM, Hartley C, Herrera C, Hesketh A, Heyburn D, Hill V, Hiscox JA, Holden M, Holmes A, Holmes N, Holt GS, Hopes R, Hosmillo M, Houldcroft CJ, Howson-Wells H, Hubb J, Hughe J, Hughes Met al., 2020, An integrated national scale SARS-CoV-2 genomic surveillance network, The Lancet Microbe, Vol: 1, Pages: E99-E100, ISSN: 2666-5247

Journal article

Rowan AG, Dillon R, Witkover A, Melamed A, Demontis M-A, Gillet NA, Mun LJ, Bangham CRM, Cook LB, Fields PA, Taylor GPet al., 2020, Evolution of retrovirus-infected premalignant T-cell clones prior to Adult T-cell leukemia/lymphoma diagnosis, Blood, Vol: 135, Pages: 2023-2032, ISSN: 0006-4971

Adult T cell leukemia/lymphoma (ATL) is an aggressive hematological malignancy caused by Human T-cell leukemia virus type-1 (HTLV-1). ATL is preceded by decades of chronic HTLV-1 infection, and the tumors carry both somatic mutations and proviral DNA integrated into the tumor genome. In order to gain insight into the oncogenic process, we used targeted sequencing to track the evolution of the malignant clone in six individuals, 2-10 years before the diagnosis of ATL. Clones of premalignant HTLV-1-infected cells bearing known driver mutations were detected in the blood up to 10 years before individuals developed acute and lymphoma subtype ATL. Six months before diagnosis, the total number and variant allele fraction of mutations increased in the blood. Peripheral blood mononuclear cells from premalignant cases (1 year pre-diagnosis) had significantly higher mutational burden in genes frequently mutated in ATL than did high risk, age-matched HTLV-1-carriers who remained ATL-free after a median of 10 years of follow up. These data show that HTLV-1-infected T cell clones carrying key oncogenic driver mutations can be detected in cases of ATL years before the onset of symptoms. Early detection of such mutations may enable earlier and more effective intervention to prevent the development of ATL.

Journal article

Cook LBM, Rowan AG, 2020, CD28 fusions: an opportunity for young ATL?, BLOOD, Vol: 135, Pages: 1415-1416, ISSN: 0006-4971

Journal article

Wolf S, Haddow J, Greiller C, Taylor G, Cook L, Rowan Aet al., 2020, Finding the five percent: predicting adult T-cell leukaemia/lymphoma (ATLL) in human T-cell leukaemia virus-1 (HTLV-1) carriers using a novel flow cytometric method, 60th Annual Scientific Meeting of the British-Society-for-Haematology (BSH), Publisher: WILEY, Pages: 105-106, ISSN: 0007-1048

Conference paper

Saeed Z, Rowan A, Greiller C, Taylor G, Pollock Ket al., 2020, Enhanced T-cell maturation and monocyte aggregation are features of cellular inflammation in human T-lymphotropic virus type-1-associated myelopathy, Clinical Infectious Diseases, Vol: 70, Pages: 1326-1335, ISSN: 1058-4838

BackgroundHuman T-lymphotropic virus type-1 (HTLV-1) associated myelopathy (HAM), is an inflammatory condition characterised by severe disability and high levels of infected white blood cells. The circulating cellular inflammatory changes that distinguish this condition from asymptomatic infection are not well understood.MethodsTo investigate the immune characteristics of individuals with low or high HTLV-1 proviral load (pVL), symptomatic disease and the impact of immunosuppressive therapy, thirty-eight women living with HTLV-1 infection, with a median age 59 (52-68) years were studied. Nineteen were asymptomatic carriers, with low or high pVL, and nineteen were diagnosed with HAM, with ten receiving anti-inflammatory therapy. Peripheral blood mononuclear cells were stained and analysed for frequency distribution and activation of innate and adaptive immune cell subsets using multi-parameter flow cytometry.ResultsInflation of the CD4:CD8 ratio (>2) was observed amongst all groups irrespective of pVL. The frequency of naïve CD4+ T-cells correlated inversely with HTLV-1 pVL (rs=-0.344, p=0.026). Mature TEM CD4+ T-cells were expanded in patients with untreated HAM compared with asymptomatic carriers (p<0.001), but less so in those on therapy. High levels of exhausted (PD-1+) and senescent (CD28null) CD4+ and CD8+ T-cells were observed in all individuals particularly in those with HAM, whilst monocytes showed increased aggregation, and CD14+CD56- monocytes were less frequent.ConclusionsCD4:CD8 ratio inflation is a feature of HTLV-1 infection, whereas enhanced CD4+ T-cell maturation and monocyte aggregation are features of HAM reflecting widespread inflammatory change, which may be detectable pre-symptomatically, and be amenable to anti-inflammatory treatment.

Journal article

Cook LBM, Demontis MA, Sagawe S, Witkover A, Melamed A, Turpin J, Dillon R, Haddow J, Marks AJ, Bangham CRM, Fields P, Taylor GP, Rowan AGet al., 2019, Molecular remissions are observed in chronic adult T-cell leukemia/lymphoma in patients treated with mogamulizumab, Haematologica, Vol: 104, Pages: e566-e569, ISSN: 0390-6078

Journal article

Mulherkar R, Karabudak A, Huang X, Philip R, Ginwala R, Rowan A, Khan Z, Jain Pet al., 2019, Immunogenicity of novel MHC Class I epitopes for a therapeutic vaccine against HTLV-1, 16th International Symposium on NeuroVirology, Publisher: SPRINGER, Pages: S31-S32, ISSN: 1355-0284

Conference paper

Cook L, Demontis MA, Sagawe S, Witkover A, Melamed A, Turpin J, Haddow J, Wolf S, Marks S, Bangham C, Fields P, Taylor G, Rowan Aet al., 2019, Molecular remissions are observed in chronic adult T-cell leukaemia/lymphoma in patients treated with mogamulizumab, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 185, Pages: 172-173, ISSN: 0007-1048

Journal article

Mulherkar R, Karabudak A, Ginwala R, Huang X, Rowan A, Philip R, Murphy EL, Clements D, Ndhlovu LC, Khan ZK, Jain Pet al., 2018, In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection, VACCINE, Vol: 36, Pages: 5046-5057, ISSN: 0264-410X

Journal article

Katsuya H, Cook LB, Rowan A, Satou Y, Taylor G, Bangham CRMet al., 2018, Phosphatidylinositol 3-kinase-delta (PI3K-delta) is a potential therapeutic target in adult T-cell leukemia-lymphoma, Biomarker Research, Vol: 6, ISSN: 2050-7771

The prognosis of adult T-cell leukemia-lymphoma (ATL) remains very poor, and there is an urgent clinical need to investigate novel therapies for ATL. The expression of phosphatidylinositol 3-kinase-δ (PI3k-δ) is normally restricted to hematopoietic cells and is known as a key determinant of cell survival in certain cancers. The inhibitor of PI3k-δ, idelalisib, has been shown to be effective in the treatment of chronic lymphocytic leukemia. Here, we report the expression of PI3k-δ and the ability of idelalisib to promote apoptosis in ex vivo ATL samples. The activity of PI3K was quantified by a PI3-Kinase Activity ELISA kit. Although there was no significant difference in mean PI3K activity between healthy donors and patients with ATL, certain cases of ATL showed extremely high PI3K activities. The expression of PI3k-δ protein was detectable in most ATL cases. The freshly isolated cells from ATL patients were cultured with or without idelalisib for 0–10 days, and cell survival was then quantified. Idelalisib induced apoptosis in ATL cells in a time-dependent manner, and significantly reduced the frequency of viable ATL cells at 10 days. No time-dependent effects of idelalisib were observed in non-malignant T cells from the same patients. CCL22 has been reported to promote survival of ATL cells in part through the PI3K-AKT pathway. Idelalisib blocked this CCL22-induced phosphorylation of AKT and significantly inhibited the proliferation of ATL cells. These results validate the PI3K-AKT pathway as a potential therapeutic target in ATL.

Journal article

Mulherkar R, Karabudak A, Huang X, Rowan A, Philip R, Jain Pet al., 2018, Immunogenicity of novel MHC Class I epitopes to confer protective immunity against chronic HTLV-1 infection, Publisher: SPRINGER, Pages: S59-S60, ISSN: 1557-1890

Conference paper

Mulherkar R, Karabudak A, Huang X, Rowan A, Philip R, Jain Pet al., 2018, Immunogenicity of novel MHC Class I epitopes to confer protective immunity against chronic HTLV-1 infection, Joint Meeting of the International-Society-for-NeuroVirology (ISNV) and the Society-on-NeuroImmune-Pharmacology (SNIP), Publisher: SPRINGER, Pages: S59-S60, ISSN: 1355-0284

Conference paper

Cook LB, Rowan A, Demontis M, Sagawe S, Gillet N, Melamed A, Greiller C, Witkover A, Bangham C, Taylor GPet al., 2017, Long-term clinical remission maintained after cessation of zidovudine and interferon-α therapy in chronic adult T-cell leukemia/lymphoma, International Journal of Hematology, Vol: 107, Pages: 378-382, ISSN: 0925-5710

Globally, > 5–10 million people are estimated to be infected with Human T-lymphotropic virus type 1 (HTLV-1), of whom ~ 5% develop adult T-cell leukemia/lymphoma (ATL). Despite advances in chemotherapy, overall survival (OS) has not improved in the 35 years since HTLV-1 was first described. In Europe/USA, combination treatment with zidovudine and interferon-α (ZDV/IFN-α) has substantially changed the management of patients with the leukemic subtypes of ATL (acute or unfavorable chronic ATL) and is under clinical trial evaluation in Japan. However, there is only a single published report of long-term clinical remission on discontinuing ZDV/IFN-α therapy and the optimal duration of treatment is unknown. Anecdotal cases where therapy is discontinued due to side effects or compliance have been associated with rapid disease relapse, and it has been widely accepted that the majority of patients will require life-long therapy. The development of molecular methods to quantify minimal residual disease is essential to potentially guide therapy for individual patients. Here, for the first time, we report molecular evidence that supports long-term clinical remission in a patient who was previously treated with ZDV/IFN-α for 5 years, and who has now been off all therapy for over 6 years.

Journal article

Cook LB, Rowan AG, Demontis MA, Marks S, Bangham CRM, Fields P, Taylor GPet 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: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Rowan AG, Witkover A, Melamed A, Tanaka Y, Cook LBM, Fields P, Taylor GP, Bangham CRMet 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.

Journal article

Manivannan K, Rowan AG, Tanaka Y, Taylor GP, Bangham CRMet 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.

Journal article

Satou Y, Miyazato P, Ishihara Y, Yaguchi H, Melamed A, Miura M, Fukuda A, Nosaka K, Watanabe T, Rowan A, Nakao M, Bangham Cet 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.

Journal article

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.

Book chapter

Bangham CRM, Melamed A, Laydon D, Al Khatib H, Rowan A, Taylor Get 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.

Journal article

Satou Y, Paola M, Ishihara K, Fukuda A, Nosaka K, Watanabe T, Rowan A, Nakao M, Bangham CRMet al., 2015, HTLV-1 inserts an ectopic CTCF-binding site into the human genome, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690

Conference paper

Rowan AG, Fields P, Taylor GP, Bangham CRMet 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

Conference paper

Kagdi H, Rowan A, Demontis MA, Bangham C, Taylor Get al., 2015, Molecular characterization of heterogeneity in adult T-cell leukaemia/lymphoma, Publisher: BioMed Central, ISSN: 1742-4690

Conference paper

Manivannan K, Rowan AG, Taylor GP, Bangham CRMet al., 2015, Tumor suppressor in lung cancer identifies latency infected cells in non malignant HTLV-1 infection, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690

Conference paper

Melamed A, Yaguchi H, Rowan A, Cook L, Bangham CRMet al., 2015, Comparative analysis of gene expression patterns in the HTLV-1 infected T-cell clones, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690

Conference paper

Yaguchi H, Melamed A, Rowan A, Cook L, Satou Y, Bangham CRMet al., 2015, Identification of long-range chromatin interactions between HTLV-1 and the host genome, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690

Conference paper

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