Imperial College London

Professor Graham P Taylor

Faculty of MedicineDepartment of Infectious Disease

Professor of Human Retrovirology
 
 
 
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Contact

 

+44 (0)20 7594 3910g.p.taylor Website

 
 
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Location

 

443Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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516 results found

Ramesh N, Cockbain B, Taylor GP, Rosadas de Oliveira Cet al., 2024, How do socioeconomic determinants of health affect the likelihood of living with HTLV-1 globally? A systematic review with meta-analysis, Frontiers in Public Health, Vol: 12, ISSN: 2296-2565

Introduction: Human T Lymphotropic Virus type 1 (HTLV-1) is a neglected retrovirus associated with many clinical disorders, most notably Adult T-cell Leukemia/Lymphoma and HTLV-1-Associated Myelopathy (HAM). Found in endemic clusters across the world, high prevalence has been reported in minoritized groups who suffer from health inequities. This study investigates the association between HTLV-1 prevalence and the following socioeconomic determinants of health: education, income, and employment, which are markers of health inequity.Methods: A systematic review was conducted by searching the following databases: Ovid/Medline, Embase, Global Health Database, Web of Science, LILACS and SciELO. Primary studies in English, Spanish and Portuguese mentioning HTLV-1 and one of education, income and/or employment were included. A random-effects meta-analysis was performed, and odds ratios (OR) were calculated to determine the association between these socioeconomic determinants of health and HTLV-1 prevalence.Results: 42 studies were included. The likelihood of having HTLV-1 was higher in individuals with less than completed primary education compared to those who completed primary education (OR 1.86 [95% CI 1.34–2.57]; p < 0.01). This may be because individuals with low education have reduced access to and understanding of health information, thus increasing the prevalence of risk factors associated with HTLV-1 infection. No other determinants were found to be statistically significant.Conclusion: Fewer years of schooling are associated with increased likelihood of contracting HTLV-1. Therefore, health promotion materials and public health policies regarding HTLV-1 must consider those with lower educational levels to effectively reduce disease transmission.

Journal article

Maher A, Aristodemou A, Giang N, Tanaka Y, Bangham C, Taylor G, Dominguez-Villar Met al., 2024, HTLV-1 induces an inflammatory CD4+CD8+ T cell population in HTLV-1-associated myelopathy, Journal of Clinical Investigation Insight, Vol: 9, ISSN: 0021-9738

Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus with preferential CD4+ T cell tropism that causes a range of conditions spanning from asymptomatic infection to adult T-cell leukemia and HTLV-1-associated myelopathy (HAM), an inflammatory disease of the CNS. The mechanisms by which HTLV-1 induces HAM are poorly understood. By directly examining the ex vivo phenotype and function of T cells from asymptomatic carriers and patients with HAM, we show that patients with HAM have a higher frequency of CD4+CD8+ double positive (DP) T cells, which are infected with HTLV-1 at higher rates than CD4+ T cells. Displaying both helper and cytotoxic phenotypes, these DP T cells are highly pro-inflammatory and contain high frequencies of HTLV-1-specific cells. Mechanistically, we demonstrate that DP T cells arise by direct HTLV-1 infection of CD4+ and CD8+ T cells. High levels of CD49d and CXCR3 expression suggest that DP T cells possess the ability to migrate to the CNS, and when co-cultured with astrocytes, DP T cells induce proinflammatory astrocytes that express high levels of CXCL10, IFN-, and IL-6. These results demonstrate the potential of DP T cells to directly contribute to CNS pathology.

Journal article

De Mendoza C, Taylor G, Gessain A, Thoma-Kress AK, Bangham C, Vesterbacka J, Accolla R, Bazarbachi A, Van Weyenbergh J, Cook L, Casseb J, Ramos JC, Rosadas C, Macchi B, Cassar O, Soriano Vet al., 2024, Virology, pathogenesis, epidemiology and clinical management of HTLV-1 infection. Proceedings of the 30th HTLV European research network (HERN 2023), Journal of Osteopathic Medicine

The 30th workshop of the HTLV European Research Network (HERN) was held in Madrid on September 15-16, 2023. Over fifty researchers from Europe and America convened for a two-day conference to update and discuss basic science, epidemiology, clinical management and therapeutics for patients with HTLV-1 infection. Scientific topics addressed included new estimates for HTLV-1 in Europe; impact of antenatal screening on mother-to-child HTLV-1 infections; new insights into the molecular epidemiology of HTLV-1; reports of elite controllers for HTLV-1 infection; role of antiretrovirals as HTLV-1 pre-exposure prophylaxis; and prospects for a HTLV-1 vaccine. The group agreed to submit a formal request to WHO for increasing the global surveillance and awareness of HTLV-1. This viral infection is a potentially life-threatening, neglected condition with neither treatment nor vaccine. At this time, expanding HTLV-1 screening is the most effective way to reduce viral dissemination.

Journal article

Costigan D, Fenn J, Yen S, Ilott N, Bullers S, Hale J, Greenhalf W, Conibear E, Koycheva A, Madon K, Jahan I, Huang M, Badhan A, Parker E, Rosadas C, Jones K, McClure M, Tedder R, Taylor G, Baillie KJ, Semple MG, Openshaw PJM, Pearson C, Johnson J, INSTINCT Study Group, ISARIC4C investigators, Lalvani A, Thornton EEet al., 2023, A pro-inflammatory gut mucosal cytokine response is associated with mild COVID-19 disease and superior induction of serum antibodies, Mucosal Immunology, ISSN: 1933-0219

The relationship between gastrointestinal tract infection, the host immune response, and the clinical outcome of disease is not well understood in COVID-19. We sought to understand the effect of intestinal immune responses to SARS-CoV-2 on patient outcomes including the magnitude of systemic antibody induction. Combining two prospective cohort studies, International Severe Acute Respiratory and emerging Infections Consortium Comprehensive Clinical Characterisations Collaboration (ISARIC4C) and Integrated Network for Surveillance, Trials and Investigations into COVID-19 Transmission (INSTINCT), we acquired samples from 88 COVID-19 cases representing the full spectrum of disease severity and analysed viral RNA and host gut cytokine responses in the context of clinical and virological outcome measures. There was no correlation between the upper respiratory tract and faecal viral loads. Using hierarchical clustering, we identified a group of fecal cytokines including Interleukin-17A, Granulocyte macrophage colony-stimulating factor, Tumor necrosis factorα, Interleukin-23, and S100A8, that were transiently elevated in mild cases and also correlated with the magnitude of systemic anti-Spike-receptor-binding domain antibody induction. Receiver operating characteristic curve analysis showed that expression of these gut cytokines at study enrolment in hospitalised COVID-19 cases was associated negatively with overall clinical severity implicating a protective role in COVID-19. This suggests that a productive intestinal immune response may be beneficial in the response to a respiratory pathogen and a biomarker of a successful barrier response.

Journal article

Ren R, Cai S, Fang X, Wang X, Zhang Z, Damiani M, Hudlerova C, Rosa A, Hope J, Cook NJ, Gorelkin P, Erofeev A, Novak P, Badhan A, Crone M, Freemont P, Taylor GP, Tang L, Edwards C, Shevchuk A, Cherepanov P, Luo Z, Tan W, Korchev Y, Ivanov AP, Edel JBet al., 2023, Multiplexed detection of viral antigen and RNA using nanopore sensing and encoded molecular probes, Nature Communications, Vol: 14, ISSN: 2041-1723

We report on single-molecule nanopore sensing combined with position-encoded DNA molecular probes, with chemistry tuned to simultaneously identify various antigen proteins and multiple RNA gene fragments of SARS-CoV-2 with high sensitivity and selectivity. We show that this sensing strategy can directly detect spike (S) and nucleocapsid (N) proteins in unprocessed human saliva. Moreover, our approach enables the identification of RNA fragments from patient samples using nasal/throat swabs, enabling the identification of critical mutations such as D614G, G446S, or Y144del among viral variants. In particular, it can detect and discriminate between SARS-CoV-2 lineages of wild-type B.1.1.7 (Alpha), B.1.617.2 (Delta), and B.1.1.539 (Omicron) within a single measurement without the need for nucleic acid sequencing. The sensing strategy of the molecular probes is easily adaptable to other viral targets and diseases and can be expanded depending on the application required.

Journal article

Cockbain B, Taylor GP, Rosadas de Oliveira C, 2023, HTLV-1 as a contributing factor towards scabies and its systemic sequelae, Journal of Global Health, ISSN: 2047-2978

It is increasingly recognised that scabies plays an important, causative role in the development of group A Streptococcal (GAS) skin infections, with the renal and cardiac sequelae of these infections leading to significant global morbidity and mortality. There remains, however, uncertainty as to why scabies is so prevalent in certain areas. In this Viewpoint, we propose that Human T-Lymphotropic virus type 1 (HTLV-1) may be one contributing factor, as HTLV-1 can increase an individual’s susceptibility to scabies and, through its association with the highly infectious crusted scabies, may help maintain scabies within populations. HTLV-1 may also contribute to the global burden of GAS skin infections even in the absence of scabies, as HTLV-1 is associated with other causes of skin barrier breakdown, including xerosis and infective dermatitis of HTLV-1. Through its role in the development of GAS skin infections, HTLV-1 may be an important, yet thus far unappreciated, contributor towards the global burden of renal and cardiac disease.

Journal article

Rosadas de Oliveira C, Harvala H, Davison K, Taylor Get al., 2023, HTLV-1 screening of blood donations: we are systematically missing opportunities, British Journal of Haematology, Vol: 202, Pages: 1220-1223, ISSN: 0007-1048

Journal article

Adonis A, Russell A-M, Taylor GP, Preston M, Shields A, Strachan S, Young S, Diallo H, Ashford S, Cassidy Eet al., 2023, Patient research priority setting partnership in human T-cell lymphotropic virus type I, HEALTH EXPECTATIONS, ISSN: 1369-6513

Journal article

Davies NWS, Taylor GP, 2023, Targeted immunotherapy for HTLV-1-associated myelopathy: a step in the right direction, BRAIN, Vol: 146, Pages: 3114-3116, ISSN: 0006-8950

Journal article

Rosadas C, Senna K, da Costa M, Assone T, Casseb J, Nukui Y, Cook L, Mariano L, Galvão-Castro B, Rios Grassi MF, Penalva de Oliveira AC, Caterino-de-Araujo A, Malik B, Boa-Sorte N, Peixoto P, Puccioni-Sohler M, Santos M, Taylor GPet al., 2023, Women living with HTLV-1 should have the opportunity to make informed decisions on prevention of mother-to-child transmission, The Lancet Global Health, Vol: 11, Pages: e1181-e1181, ISSN: 2214-109X

Journal article

Eales O, de Oliveira Martins L, Page A, Wang H, Bodinier B, Tang D, Haw D, Jonnerby LJA, Atchison C, Ashby D, Barclay W, Taylor G, Cooke G, Ward H, Darzi A, Riley S, Elliott P, Donnelly C, Chadeau Met al., 2023, Dynamics and scale of the SARS-CoV-2 variant Omicron epidemic in England, Nature Communications, Vol: 13, ISSN: 2041-1723

The SARS-CoV-2 pandemic has been characterised by the regular emergence of genomic variants. With natural and vaccine-induced population immunity at high levels, evolutionary pressure favours variants better able to evade SARS-CoV-2 neutralising antibodies. The Omicron variant (first detected in November 2021) exhibited a high degree of immune evasion, leading to increased infection rates worldwide. However, estimates of the magnitude of this Omicron wave have often relied on routine testing data, which are prone to several biases. Using data from the REal-time Assessment of Community Transmission-1 (REACT-1) study, a series of cross-sectional surveys assessing prevalence of SARS-CoV-2 infection in England, we estimated the dynamics of England’s Omicron wave (from 9 September 2021 to 1 March 2022). We estimate an initial peak in national Omicron prevalence of 6.89% (5.34%, 10.61%) during January 2022, followed by a resurgence in SARS-CoV-2 infections as the more transmissible Omicron sub-lineage, BA.2 replaced BA.1 and BA.1.1. Assuming the emergence of further distinct variants, intermittent epidemics of similar magnitudes may become the ‘new normal’.

Journal article

Aristodemou AENR, Rueda D, Taylor GR, Bangham CRM, Green PLRet al., 2023, The transcriptome of HTLV-1-infected primary cells following reactivation reveals changes to host gene expression central to the proviral life cycle, PLoS Pathogens, Vol: 19, ISSN: 1553-7366

Infections by Human T cell Leukaemia Virus type 1 (HTLV-1) persist for the lifetime of the host by integrating into the genome of CD4+ T cells. Proviral gene expression is essential for proviral survival and the maintenance of the proviral load, through the pro-proliferative changes it induces in infected cells. Despite their role in HTLV-1 infection and a persistent cytotoxic T lymphocyte response raised against the virus, proviral transcripts from the sense-strand are rarely detected in fresh cells extracted from the peripheral blood, and have recently been found to be expressed intermittently by a small subset of cells at a given time. Ex vivo culture of infected cells prompts synchronised proviral expression in infected cells from peripheral blood, allowing the study of factors involved in reactivation in primary cells. Here, we used bulk RNA-seq to examine the host transcriptome over six days in vitro, following proviral reactivation in primary peripheral CD4+ T cells isolated from subjects with non-malignant HTLV-1 infection. Infected cells displayed a conserved response to reactivation, characterised by discrete stages of gene expression, cell division and subsequently horizontal transmission of the virus. We observed widespread changes in Polycomb gene expression following reactivation, including an increase in PRC2 transcript levels and diverse changes in the expression of PRC1 components. We hypothesize that these transcriptional changes constitute a negative feedback loop that maintains proviral latency by re-deposition of H2AK119ub1 following the end of proviral expression. Using RNAi, we found that certain deubiquitinases, BAP1, USP14 and OTUD5 each promote proviral transcription. These data demonstrate the detailed trajectory of HTLV-1 proviral reactivation in primary HTLV-1-carrier lymphocytes and the impact on the host cell.

Journal article

Zhang Y, Yan AWC, Boelen L, Hadcocks L, Salam A, Gispert DP, Spanos L, Bitria LM, Nemat-Gorgani N, Traherne JA, Roberts C, Koftori D, Taylor GP, Forton D, Norman PJ, Marsh SGE, Busch R, Macallan DC, Asquith Bet al., 2023, KIR-HLA interactions extend human CD8+T cell lifespan in vivo, JOURNAL OF CLINICAL INVESTIGATION, Vol: 133, ISSN: 0021-9738

Journal article

Derqui N, Koycheva A, Zhou J, Pillay TD, Crone MA, Hakki S, Fenn J, Kundu R, Varro R, Conibear E, Madon KJ, Barnett JL, Houston H, Singanayagam A, Narean JS, Tolosa-Wright MR, Mosscrop L, Rosadas C, Watber P, Anderson C, Parker E, Freemont PS, Ferguson NM, Zambon M, McClure MO, Tedder R, Barclay WS, Dunning J, Taylor GP, Lalvani A, INSTINCT and ATACCC study groupet al., 2023, Risk factors and vectors for SARS-CoV-2 household transmission: a prospective, longitudinal cohort study, The Lancet Microbe, Vol: 4, Pages: e397-e408, ISSN: 2666-5247

BACKGROUND: Despite circumstantial evidence for aerosol and fomite spread of SARS-CoV-2, empirical data linking either pathway with transmission are scarce. Here we aimed to assess whether the presence of SARS-CoV-2 on frequently-touched surfaces and residents' hands was a predictor of SARS-CoV-2 household transmission. METHODS: In this longitudinal cohort study, during the pre-alpha (September to December, 2020) and alpha (B.1.1.7; December, 2020, to April, 2021) SARS-CoV-2 variant waves, we prospectively recruited contacts from households exposed to newly diagnosed COVID-19 primary cases, in London, UK. To maximally capture transmission events, contacts were recruited regardless of symptom status and serially tested for SARS-CoV-2 infection by RT-PCR on upper respiratory tract (URT) samples and, in a subcohort, by serial serology. Contacts' hands, primary cases' hands, and frequently-touched surface-samples from communal areas were tested for SARS-CoV-2 RNA. SARS-CoV-2 URT isolates from 25 primary case-contact pairs underwent whole-genome sequencing (WGS). FINDINGS: From Aug 1, 2020, until March 31, 2021, 620 contacts of PCR-confirmed SARS-CoV-2-infected primary cases were recruited. 414 household contacts (from 279 households) with available serial URT PCR results were analysed in the full household contacts' cohort, and of those, 134 contacts with available longitudinal serology data and not vaccinated pre-enrolment were analysed in the serology subcohort. Household infection rate was 28·4% (95% CI 20·8-37·5) for pre-alpha-exposed contacts and 51·8% (42·5-61·0) for alpha-exposed contacts (p=0·0047). Primary cases' URT RNA viral load did not correlate with transmission, but was associated with detection of SARS-CoV-2 RNA on their hands (p=0·031). SARS-CoV-2 detected on primary cases' hands, in turn, predicted contacts' risk of infection (adjusted relative risk [aRR]=1·70 [95% CI 1·24-2·3

Journal article

Lees EA, Tickner N, Lyall H, Mcmaster P, Smith B, Cliffe L, Taylor G, Foster Cet al., 2023, Infant postnatal prophylaxis following maternal viraemia during breastfeeding, AIDS, Vol: 37, Pages: 1185-1186, ISSN: 0269-9370

Journal article

Dixon L, McNamara C, Dhasmana D, Taylor G, davies Net al., 2023, The imaging spectrum of HTLV-1 related neurological disease: a pooled series and review, Neurology: Clinical Practice, Vol: 13, Pages: 1-11, ISSN: 2163-0402

Purpose of Review Human T-cell lymphotropic virus type 1 (HTLV-1)–associated myelopathy (HAM) is a well-recognized neurologic complication of HTLV-1. Beyond HAM, several other neurologic manifestations are increasingly recognized, including acute myelopathy, encephalopathy, and myositis. The clinical and imaging features of these presentations are less well understood and potentially underdiagnosed. In this study, we summarize the imaging features of HTLV-1–related neurologic disease, providing both a pictorial review and pooled series of the less well-recognized presentations.Recent Findings 35 cases of acute/subacute HAM and 12 cases of HTLV-1–related encephalopathy were found. In subacute HAM, cervical and upper thoracic longitudinally extensive tranverse myelitis was noted, while in HTLV-1–related encephalopathy, confluent lesions in the frontoparietal white matter and along the corticospinal tracts were the most prevalent finding.Summary There are varied clinical and imaging presentations of HTLV-1–related neurologic disease. Recognition of these features aids early diagnosis where therapy may have the greatest benefit.

Journal article

Rosadas C, Taylor GP, 2023, Pre-analytical long-term stability of neopterin and neurofilament light in stored cerebrospinal fluid samples, Clinical Chemistry and Laboratory Medicine, Vol: 61, Pages: 1230-1234, ISSN: 1434-6621

ObjectivesThe aim of this study was to evaluate the impact of long-term sample storage on the concentrations of neopterin and neurofilament light (Nfl) in cerebrospinal fluid (CSF) samples. These are useful markers of neuroinflammation and neuronal damage and have been applied as biomarkers for several neurological diseases. However, different pre-analytical variables have potential to influence results.MethodsTwenty-one CSF samples donated by patients with HTLV-1-associated myelopathy (HAM) and stored for up to 11 years at −80 °C were retested after three-years for neopterin (n=10) and Nfl (n=11) by ELISA.ResultsThere was a strong correlation between the paired results (r>0.98, p<0.0001). Neopterin concentrations (nmol/L) ranged from 12.4 to 64 initially and from 11.5 to 64.4 when retested, with means (SD) of 30 (18.4) 1st test and 33 (19.1) 2nd test. Nfl concentrations (pg/mL) ranged from 79.9 to 3,733 initially and from 86.3 to 3,332, when retested with means (SD) of 1,138 (1,272) 1st test and 1,009 (1,114) at re-test.ConclusionsStoring CSF samples at −80 °C appears not to impact the quantification of neopterin and Nfl allowing confidence in the reporting of archived samples.

Journal article

Short C-E, 2023, Comparative analysis of vaginal microbiota sampling using menstrual cups and high vaginal swabs in pregnant women living with HIV-1 infection, Frontiers in Cellular and Infection Microbiology, Vol: 13, ISSN: 2235-2988

Background: Menstrual cups (MCs) are increasingly used to collect cervicovaginal secretions to characterise vaginal mucosal immunology, in conjunction with high vaginal swabs (HVS) for metataxonomics, particularly in HIV transmission studies. We hypothesised that both methods of collecting bacterial biomass are equivalent for 16S rRNA gene sequencing.Material and Methods: Cervicovaginal fluid (CVF) samples from 16 pregnant women with HIV-1 (PWWH) were included to represent the major vaginal bacterial community state types (CST I-V). Women underwent sampling during the second trimester by liquid amies HVS followed by a MC (Soft disc™) and samples were stored at -80°C. Bacterial cell pellets obtained from swab elution and MC (500 µL, 1 in 10 dilution) were resuspended in 120 µL PBS for DNA extraction. Bacterial 16S rRNA gene sequencing was performed using V1-V2 primers and were analysed using MOTHUR. Paired total DNA, bacterial load, amplicon read counts, diversity matrices and bacterial taxa were compared by sampling method using MicrobiomeAnalyst, SPSS and R.Results: The total DNA eluted from one aliquot of diluted CVF from an MC was similar to that of a HVS (993ng and 609ng, p=0.18); the mean bacterial loads were also comparable for both methods (MC: 8.0 log10 16S rRNA gene copies versus HVS: 7.9 log10 16S rRNA gene copies, p=0.27). The mean number of sequence reads generated from MC samples was lower than from HVS (MC: 12730; HVS:14830, p=0.05). The α-diversity metrices were similar for both techniques; MC Species Observed: 41 (range 12-96) versus HVS: 47 (range 16-96), p=0.15; MC Inverse Simpson Index: 1.98 (range 1.0-4.0) versus HVS: 0.48 (range 1.0-4.4), p=0.22). The three most abundant species observed were: Lactobacillus iners, Lactobacillus crispatus and Gardnerella vaginalis. Hierarchical clustering of relative abundance data showed that samples obtained using different techniques in an individual clustered in the same CST group.

Journal article

Rosadas C, Senna K, da Costa M, Assone T, Casseb J, Nukui Y, Cook L, Mariano L, Galvão Castro B, Rios Grassi MF, Penalva de Oliveira AC, Caterino-de-Araujo A, Malik B, Boa-Sorte N, Peixoto P, Puccioni-Sohler M, Santos M, Taylor GPet al., 2023, Economic analysis of antenatal screening for human T-cell lymphotropic virus type 1 in Brazil: an open access cost-utility model, The Lancet Global Health, Vol: 11, Pages: e781-e790, ISSN: 2214-109X

BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes severe diseases, such as aggressive cancer or progressive neurological disease. HTLV-1 affects mainly people in areas with low human development index and can be transmitted from mother to child, primarily through breastfeeding. Refraining from breastfeeding is an effective intervention to reduce the risk of infection in infants. However, HTLV-1 antenatal screening is not offered globally. According to WHO, the scarcity of cost-effectiveness studies is considered one of the major barriers to the implementation of policies to prevent HTLV-1 infection. Therefore, this study aimed to assess the cost-effectiveness of antenatal screening and postnatal interventions to prevent HTLV-1 mother-to-child transmission in Brazil and to develop an open-access, editable, mathematical model that can be used by other countries and regions to assess different scenarios. METHODS: In this cost-utility analysis, we constructed a decision tree and a Markov model to assess the cost-effectiveness of HTLV-1 antenatal screening and postnatal interventions (ie, avoidance of breastfeeding, by suppression of lactation with cabergoline, and provision of formula feed) to reduce transmission. For our model, we used data from Brazil and we took the perspective of the public health-care system to estimate costs. FINDINGS: The implementation of both screening and interventions would result in the prevention of 1039 infections in infants every year in Brazil with an incremental cost-effectiveness ratio (ICER) of US$11 415 per quality-adjusted life-year (QALY). 88% of all probabilistic sensitivity analysis simulations had ICER values lower than the Brazilian cost-effectiveness threshold ($18 107·74 per QALY). HTLV-1 prevalence in pregnant women, the risk of HTLV-1 transmission when breastfeeding lasts for 6 months or more, and the cost of screening tests were the variables with the largest effect on ICER. INT

Journal article

Khan M, Bradshaw D, Brown CS, Haddow J, Patel P, Tosswill JHC, Pollock K, Elliott T, Wang X, Alagaratnam J, Mora-Peris B, Kaye S, McClure MO, Muir D, Randell P, Taylor GP, Fidler SJet al., 2023, Characterization of rare spontaneous human immunodeficiency virus viral controllers attending a national United Kingdom clinical service using a combination of serology and molecular diagnostic assays, Open Forum Infectious Diseases, Vol: 10, ISSN: 2328-8957

BACKGROUND: We report outcomes and novel characterization of a unique cohort of 42 individuals with persistently indeterminate human immunodeficiency virus (HIV) status, the majority of whom are HIV viral controllers. METHODS: Eligible individuals had indeterminate or positive HIV serology, but persistently undetectable HIV ribonucleic acid (RNA) by commercial assays and were not taking antiretroviral therapy (ART). Routine investigations included HIV Western blot, HIV viral load, qualitative HIV-1 deoxyribonucleic acid (DNA), coinfection screen, and T-cell quantification. Research assays included T-cell activation, ART measurement, single-copy assays detecting HIV-1 RNA and DNA, and plasma cytokine quantification. Human immunodeficiency virus seropositivity was defined as ≥3 bands on Western blot; molecular positivity was defined as detection of HIV RNA or DNA. RESULTS: Human immunodeficiency virus infection was excluded in 10 of 42 referrals, remained unconfirmed in 2 of 42, and was confirmed in 30 of 42, who were identified as HIV elite controllers (ECs), normal CD4 T-cell counts (median 820/mL, range 805-1336), and normal CD4/CD8 ratio (median 1.8, range 1.2-1.9). Elite controllers had a median duration of elite control of 6 years (interquartile range = 4-14). Antiretroviral therapy was undetected in all 23 subjects tested. Two distinct categories of ECs were identified: molecular positive (n = 20) and molecular negative (n = 10). CONCLUSIONS: Human immunodeficiency virus status was resolved for 95% of referrals with the majority diagnosed as EC. The clinical significance of the 2 molecular categories among ECs requires further investigation.

Journal article

Zhang Y, Yan AW, Boelen L, Hadcocks L, Salam A, Padrosa Gispert D, Spanos L, Mora Bitria L, Nemat-Gorgani N, Traherne JA, Roberts CH, Koftori DA, Taylor GP, Forton D, Norman PJ, Marsh SG, Busch R, Macallan D, Asquith Bet al., 2023, KIR-HLA interactions extend human CD8+ T cell lifespan in vivo., Journal of Clinical Investigation, Vol: 133, Pages: 1-33, ISSN: 0021-9738

BACKGROUND: There is increasing evidence, in transgenic mice and in vitro, that inhibitory killer cell immunoglobulin-like receptors (iKIRs) can modulate T cell responses. Furthermore, we have previously shown that iKIRs are an important determinant of T cell-mediated control of chronic virus infection and that these results are consistent with an increase in CD8+ T cell lifespan due to iKIR-ligand interactions. Here we test this prediction and investigate whether iKIRs affect T cell lifespan in humans in vivo. METHODS: We used stable isotope labelling with deuterated water to quantify memory CD8+ T cell survival in healthy individuals and patients with chronic viral infections. RESULTS: We showed that an individual's iKIR-ligand genotype is a significant determinant of CD8+ T cell lifespan: in individuals with two iKIR-ligand gene pairs, memory CD8+ T cells survived on average for 125 days, in individuals with four iKIR-ligand gene pairs then memory CD8+ T cell lifespan was doubled to 250 days. Additionally, we showed that this survival advantage is independent of iKIR expression by the T cell of interest and further that iKIR-ligand genotype altered CD8+ and CD4+ T cell immune aging phenotype. CONCLUSIONS: Together these data reveal an unexpectedly large impact of iKIR genotype on T cell survival. FUNDING: Wellcome Trust, Medical Research Council, EU Horizon 2020, EU FP7, Leukemia and Lymphoma Research, National Institute of Health Research Imperial Biomedical Research Centre, Imperial College Research Fellowship, National Institute of Health, Jefferiss Trust.

Journal article

Rowan A, Joris T, Haddow J, Taylor G, Cook Let al., 2023, Detection of HTLV-1 proviral DNA in cell-free DNA: potential for non-invasive monitoring of Adult T cell leukaemia/lymphoma using liquid biopsy?, Frontiers in Immunology, Vol: 14, Pages: 1-7, ISSN: 1664-3224

Introduction: Fragmented genomic DNA is constitutively released from dying cells into interstitial fluid in healthy tissue. In cancer, this so-called ‘cell-free’ DNA (cfDNA) released from dying malignant cells encodes cancer-associated mutations. Thus, minimally invasive sampling of cfDNA in blood plasma can be used to diagnose, characterise and longitudinally monitor solid tumours at remote sites in the body. ~5% of carriers of Human T cell leukaemia virus type 1 (HTLV-1) develop Adult T cell leukaemia/lymphoma (ATL), and a similar percentage develop an inflammatory CNS disease, HTLV-1 associated myelopathy (HAM). In both ATL and HAM, high frequencies of HTLV-1 infected cells are present in the affected tissue: each carrying an integrated DNA copy of the provirus. We hypothesised that turnover of infected cells results in the release of HTLV-1 proviruses in cfDNA, and that analysis of cfDNA from infected cells in HTLV-1 carriers might contain clinically useful information pertaining to inaccessible sites in the body- e.g. for early detection of primary or relapsing localised lymphoma type ATL. To evaluate the feasibility of this approach, we tested for HTLV-1 proviruses in blood plasma cfDNA.Methods: CfDNA (from blood plasma) and genomic DNA (gDNA, from peripheral blood mononuclear cells, PBMC) was isolated from blood from 6 uninfected controls, 24 asymptomatic carriers (AC), 21 patients with HAM and 25 patients with ATL. Proviral (HTLV-1 Tax) and human genomic DNA (the beta globin gene, HBB) targets were quantified by qPCR using primer pairs optimised for fragmented DNA.Results: Pure, high quality cfDNA was successfully extracted from blood plasma of all study participants. When compared with uninfected controls, HTLV-1 carriers had higher concentrations of cfDNA circulating in their blood plasma. Patients with ATL who were not in remission had the highest levels of blood plasma cfDNA in any group studied. HTLV-1 proviral DNA was detected in 60/70 samp

Journal article

Preda VG, Roberts LA, Quinlan RA, Short C-E, Taylor GP, Marchesi JRet al., 2023, Antiretroviral therapy (ART) inhibits the growth of cervicovaginal microbiome species in vitro: potential role in preterm birth (PTB), British HIV Association, Publisher: Wiley, Pages: 11-11, ISSN: 1464-2662

Conference paper

Preda VG, Roberts LA, Quinlan RA, Short C-ES, Taylor GP, Marchesi JRet al., 2023, Antiretroviral therapy (ART) inhibits the growth of cervicovaginal microbiome species in vitro: potential role in preterm birth (PTB), Publisher: WILEY, Pages: 11-11, ISSN: 1464-2662

Conference paper

Dustan S, Badhan A, Taylor G, 2023, Sequencing of low viral load HIV for drug resistance-associated mutations, Publisher: WILEY, Pages: 27-27, ISSN: 1464-2662

Conference paper

Shah S, Taylor G, Lyall H, Foster Cet al., 2023, Comparison of pregnancy outcomes for mothers living with perinatally acquired HIV, behaviourally acquired HIV, and those not living with HIV, Publisher: WILEY, Pages: 11-12, ISSN: 1464-2662

Conference paper

Bukasa LL, Cortina-Borja M, Peters H, Taylor GP, Thorne Cet al., 2023, Gestational diabetes in women living with HIV in the UK and Ireland: insights from population-based surveillance data, Journal of the International AIDS Society, Vol: 26, Pages: 1-10, ISSN: 1758-2652

INTRODUCTION: The prevalence of gestational diabetes (GD) is increasing globally. While universal risk factors for GD are reasonably well understood, questions remain regarding risks for women living with HIV (WLWH). We aimed to describe GD prevalence, evaluate associated maternal risk factors and assess specific birth outcomes in WLWH in the UK and Ireland. METHODS: We analysed all pregnancies (≥24 weeks' gestation) in women diagnosed with HIV before delivery, reported to the UK-based Integrated Screening Outcomes Surveillance Service between 2010 and 2020. Every report of GD was considered as a case. A multivariable logistic regression model, adjusted for women with more than one pregnancy fitted with generalized estimating equations (GEE) assessed the effect of independent risk factors. RESULTS: There were 10,553 pregnancies in 7916 women, of which 460 (4.72%) pregnancies had reported GD. Overall, the median maternal age was 33 years (Q1:29-Q3:37), and 73% of pregnancies were in Black African women. WLWH with GD (WLWH-GD) were older (61% vs. 41% aged ≥35 years, p < 0.001) and more likely to be on treatment at conception (74% vs. 64%, p < 0.001) than women without GD. WLWH-GD were more likely to have a stillbirth (odds ratio [OR]: 5.38, 95% CI: 2.14-13.5), preterm delivery (OR: 2.54, 95% CI: 1.95-3.32) and fetal macrosomia (OR: 1.14, 95% CI: 1.04-1.24). Independent risk factors for GD included estimated year of delivery (GEE-adjusted odds ratio [GEE-aOR]: 1.14, 95% CI: 1.10-1.18), advanced maternal age (≥35 years) (GEE-aOR: 2.87, 95% CI: 1.54-5.34), Asian (GEE-aOR: 2.63, 95% CI: 1.40-4.63) and Black African (GEE-aOR: 1.55, 95% CI: 1.13-2.12) ethnicity. Timing and type of antiretroviral therapy showed no evidence of a relationship with GD in multivariable analyses; however, women with a CD4 count ≤350 cells/μl were 27% less likely to have GD than women with CD4 counts >350 cells/μl (GEE-aOR: 0.73, 95% CI: 0.50-0.96). CONCLUSIONS: GD preva

Journal article

Elliott P, Whitaker M, Tang D, Eales O, Steyn N, Bodinier B, Wang H, Elliott J, Atchison C, Ashby D, Barclay W, Taylor G, Darzi A, Cooke G, Ward H, Donnelly C, Riley S, Chadeau Met al., 2023, Design and implementation of a national SARS-CoV-2 monitoring programme in England: REACT-1 Study, American Journal of Public Health, ISSN: 0090-0036

Data System. The REal-time Assessment of Community Transmission-1 (REACT-1) Study was funded by the Department of Health and Social Care in England to provide reliable and timely estimates of prevalence of SARS-CoV-2 infection by time, person and place.Data Collection/Processing. The data were obtained by writing to named individuals aged 5 years and above in random cross-sections of the population of England, using the National Health Service (NHS) list of patients registered with a general practitioner (>99% coverage) as sampling frame. Data were collected 2-3 weekly approximately every month across 19distinct rounds of data collection from May 1, 2020 to March 31, 2022.Data Analysis/Dissemination. The data and study materials are widely disseminated via the study website, preprints, publications in peer-reviewed journals and the media. Data tabulations suitably anonymised to protect participant confidentiality are available on request to the study’s Data Access Committee.Implications. The study provided inter alia real-time data on SARS-CoV-2 prevalence over time, by area, and by socio-demographic variables; estimates of vaccine effectiveness; symptom profiles and detected emergence of new variants based on viral genome sequencing.

Journal article

Rowan A, Ponnusamy K, Ren H, Taylor G, Cook L, Karadimitris Aet al., 2023, CAR-iNKT cells targeting clonal TCRVβ chains as a precise strategy to treat T cell lymphoma, Frontiers in Immunology, Vol: 14, Pages: 1-11, ISSN: 1664-3224

Introduction: Most T cell receptor (TCR)Vβ chain-expressing T cell lymphomas (TCL) including those caused by Human T cell leukaemia virus type-1 (HTLV-1) have poor prognosis. We hypothesised that chimeric antigen receptor (CAR)-mediated targeting of the clonal, lymphoma-associated TCRβ chains would comprise an effective cell therapy for TCL that would minimally impact the physiological TCR repertoire.Methods: As proof of concept, we generated CAR constructs to target four TCRVβ subunits. Efficacy of the CAR constructs was tested using conventional T cells as effectors (CAR-T). Since invariant NKT (iNKT) cell do not incite acute graft-versus-host disease and are suitable for ‘off-the-shelf’ immunotherapy, we generated anti-TCRVβ CAR-iNKT cells.Results: We show that anti-TCRVβ CAR-T cells selectively kill their cognate tumour targets while leaving >90% of the physiological TCR repertoire intact. CAR-iNKT cells inhibited the growth of TCL in vivo, and were also selectively active against malignant cells from Adult T cell leukaemia/lymphoma patients without activating expression of HTLV-1.Discussion: Thus we provide proof-of-concept for effective and selective anti-TCRVβ CAR-T and -iNKT cell-based therapy of TCL with the latter providing the option for ‘off-the-shelf’ immunotherapy.

Journal article

Bradshaw D, Khawar A, Patel P, Tosswill J, Brown C, Ogaz D, Mason E, Osman R, Mitchell H, Dosekun O, Peris BM, Pickard G, Rayment M, Jones R, Hopkins M, Williams A, Kingston M, Machin N, Taha Y, Duncan S, Turner N, Gill N, Andrews N, Raza M, Tazzyman S, Nori A, Cunningham E, Taylor GPet al., 2023, HTLV seroprevalence in people using HIV pre-exposure prophylaxis in England, JOURNAL OF INFECTION, Vol: 86, Pages: 245-247, ISSN: 0163-4453

Journal article

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