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Abstract Introduction Human T‐cell lymphotropic virus type 1 (HTLV‐1) is a chronic infection affecting 5–10 million people worldwide. Ten percent develop HTLV‐1‐associated diseases, and 3%–5% develop HTLV‐1‐associated myelopathy (HAM)/tropical spastic paraparesis. Low health‐related quality of life (HRQoL) is a significant concern for those with HTLV‐1, and little is known about how it impacts daily life or what patients need from healthcare services. To address this, we report on patient involvement workshops aimed at identifying research priorities for HTLV‐1 health service provision. Methods Participants recruited through HTLV‐1 clinics in England attended six 90‐min virtual workshops over 10 months, and two 60‐min consolidation workshops. Content developed iteratively from topic focussed group discussions. All workshops were video‐recorded with consent, transcribed verbatim and thematically analysed. Using consensus voting rounds, participants individually ranked their top six and then collectively their top three research priorities from the themes inferred from the analysis. A final feedback session explored the experiences of participating in the workshops. Findings Twenty‐seven people with HTLV‐1 engaged with the workshops with up to 22 participants attending each meeting. The majority were diagnosed with HAM (n = 22). The top three research priorities were identified as understanding disease progression, psychosocial wellbeing, and information and knowledge. Participants valued being asked to set research priorities that directly addressed their needs and enjoyed the workshops. They stressed the importance of patient advocates for promoting research that positively impacts everyday life. Conclusion This is the first of this type of research engagement with people with HTLV‐1 in the United Kingdom. Participants identified several avenues of investigation that could lead to improvements in healthcare services and HRQoL. Participants believed the workshops signified the start of a conversation to progress person‐centred and meaningful research in HTLV‐1. Patient or Public Contribution People living with HTLV‐1 were involved in the iterative design, conduct, analysis, writing and dissemination of this project through the patient involvement workshops. As a result of this engagement, a patient led advisory group has been set up to assist with the dissemination of the findings.

Abstract 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.

Human T cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects lymphocytes and causes severe diseases. HTLV-1 proviral load (PVL), i.e., the number of host cells that carry HTLV-1 proviral DNA integrated into their genome, can be measured in peripheral blood mononuclear cells (PBMCs) using quantitative polymerase chain reaction. In this narrative review, we discuss the usefulness of HTLV-1 PVL quantification and share our experience acquired during more than 30 years of follow-up of people living with HTLV-1 in the UK. Patients with HTLV-1-associated myelopathy have higher PVL than those with asymptomatic infection. This is consistent across studies in different countries. High PVL predates symptom onset for both inflammatory and proliferative diseases. High PVL is essential but not sufficient for the development of HTLV-1-associated diseases. Therefore, PVL quantification can be used to support the care of people living with HTLV-1 by identifying those most at risk of HTLV-1-associated diseases.

IntroductionHuman 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.MethodsA 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.Results42 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

(1) Background: The evidence base for the management of spontaneous viral controllers in pregnancy is lacking. We describe the management outcomes of pregnancies in a series of UK women with spontaneous HIV viral control (p = 0.10. Pre-2012 pregnancies were predominantly managed with ZDVm (28/35) with pre-labour caesarean section (PLCS) (24/35). Post-2012 4/14 received ZDVm and 10/14 triple ART, p = 0.002. Post-2012 mode of delivery was varied (5 vaginal, 6 PLCS and 3 emergency CS). No intrapartum ZDV infusions were given post-2012 compared to 11/35 deliveries pre-2012. During pregnancy, HIV was detected (> 50 copies/mL) in 14/49 pregnancies (29%) (median 92, range 51–6084). Neonatal ZDV post-exposure prophylaxis was recorded for 45/49 infants. No transmissions were reported. (4) Conclusion: UK practice has been influenced by the change in guidelines, but this has had little impact on CS rates.

Although myeloid cell dysfunction has been observed in COVID-19, the underlying mechanisms remain incompletely understood. Here, the authors demonstrate that monocytes from patients with mild to moderate COVID-19 show a blunted innate immune response and a pro-thrombotic signature following secondary SARS-CoV-2 challenge.

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 viral infection and that these results are consistent with an increase in the CD8+ T cell lifespan due to iKIR-ligand interactions. Here, we tested this prediction and investigated whether iKIRs affect T cell lifespan in humans in vivo.METHODS We used stable isotope labeling 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 was a significant determinant of CD8+ T cell lifespan: in individuals with 2 iKIR-ligand gene pairs, memory CD8+ T cells survived, on average, for 125 days; in individuals with 4 iKIR-ligand gene pairs, the memory CD8+ T cell lifespan doubled to 250 days. Additionally, we showed that this survival advantage was independent of iKIR expression by the T cell of interest and, further, that the iKIR-ligand genotype altered the CD8+ and CD4+ T cell immune aging phenotype.CONCLUSIONS Together, these data reveal an unexpectedly large effect 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 (NIHR) Imperial Biomedical Research Centre; Imperial College Research Fellowship; National Institutes of Health; Jefferiss Trust.

BackgroundMenstrual 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 MethodsCervicovaginal 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.ResultsThe 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.ConclusionThese data demonstrate that despite sampling slightly different areas of the lower genital tract, there was no difference in bacterial load or composition between methods. Both are suitable for characterisation of vaginal microbiota in PWWH. The MC offers advantages, including a higher volume of sample available for DNA extraction and complimentary assays.

Abstract 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 prevalence increased over time among WLWH but was not significantly different from the general population. Maternal age, ethnicity and CD4 count were risk factors based on available data. Stillbirth and preterm delivery were more common in WLWH‐GD than other WLWH over the study period. Further studies are required to build upon these results.

IntroductionFragmented 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.MethodsCfDNA (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.ResultsPure, 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 samples obtained from HTLV-1 carriers. The proviral load (percentage of cells carrying proviruses) was approximately tenfold lower in plasma cfDNA than in PBMC genomic DNA, and there was a strong correlation between the proviral load in cfDNA and PBMC genomic DNA in HTLV-1 carriers that did not have ATL. cfDNA samples in which proviruses were undetectable also had very low proviral load in PBMC genomic DNA. Finally, detection of proviruses in cfDNA of patients with ATL was predictive of clinical status: patients with evolving disease had higher than expected total amount of proviruses detectable in plasma cfDNA.DiscussionWe demonstrated that (1) HTLV-1 infection is associated with increased levels of blood plasma cfDNA, (2) proviral DNA is released into blood plasma cfDNA in HTLV-1 carriers and (3) proviral burden in cfDNA correlates with clinical status, raising the possibility of developing assays of cfDNA for clinical use in HTLV-1 carriers.

IntroductionMost 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.MethodsAs 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.ResultsWe 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.DiscussionThus 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.

Abstract At-home sampling is key to large scale seroprevalence studies. Dried blood spot (DBS) self-sampling removes the need for medical personnel for specimen collection but facilitates specimen referral to an appropriately accredited laboratory for accurate sample analysis. To establish a highly sensitive and specific antibody assay that would facilitate self-sampling for prevalence and vaccine-response studies. Paired sera and DBS eluates collected from 439 sero-positive, 382 sero-negative individuals and DBS from 34 vaccine recipients were assayed by capture ELISAs for IgG and IgM antibody to SARS-CoV-2. IgG and IgM combined on DBS eluates achieved a diagnostic sensitivity of 97.9% (95%CI 96.6 to 99.3) and a specificity of 99.2% (95% CI 98.4 to 100) compared to serum, displaying limits of detection equivalent to 23 and 10 WHO IU/ml, respectively. A strong correlation (r = 0.81) was observed between serum and DBS reactivities. Reactivity remained stable with samples deliberately rendered inadequate, (p = 0.234) and when samples were accidentally damaged or ‘invalid’. All vaccine recipients were sero-positive. This assay provides a secure method for self-sampling by DBS with a sensitivity comparable to serum. The feasibility of DBS testing in sero-prevalence studies and in monitoring post-vaccine responses was confirmed, offering a robust and reliable tool for serological monitoring at a population level.

While cross-reactive immunity between human coronavirus and SARS-CoV-2 may contribute to host protection, validating evidences are still scarce. Here the authors assess a cohort of 52 donors with immediate-early contact with SARS-CoV-2 to correlate higher frequency of cross-reactive T cells with lower infection rate.

The viral transactivator Tax plays a key role in HTLV-1 reactivation and de novo infection. Previous approaches focused on the histone deacetylase inhibitor (HDACi) Valproate as a latency-reversing agent to boost Tax expression and expose infected cells to the host’s immune response. However, following treatment with Valproate proviral load decreases in patients with HAM/TSP were only transient. Here, we hypothesize that other compounds, including more potent and selective HDACi, might prove superior to Valproate in manipulating Tax expression. Thus, a panel of HDACi (Vorinostat/SAHA/Zolinza, Panobinostat/LBH589/Farydak, Belinostat/PXD101/Beleodaq, Valproate, Entinostat/MS-275, Romidepsin/FK228/Istodax, and MC1568) was selected and tested for toxicity and potency in enhancing Tax expression. The impact of the compounds was evaluated in different model systems, including transiently transfected T-cells, chronically HTLV-1-infected T-cell lines, and freshly isolated PBMCs from HTLV-1 carriers ex vivo. We identified the pan-HDACi Panobinostat and class I HDACi Romidepsin as particularly potent agents at raising Tax expression. qRT-PCR analysis revealed that these inhibitors considerably boost tax and Tax-target gene transcription. However, despite this significant increase in tax transcription and histone acetylation, protein levels of Tax were only moderately enhanced. In conclusion, these data demonstrate the ability of Panobinostat and Romidepsin to manipulate Tax expression and provide a foundation for further research into eliminating latently infected cells. These findings also contribute to a better understanding of conditions limiting transcription and translation of viral gene products.

Human T cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that is endemic in a number of regions across the world. There are an estimated 5–10 million people infected worldwide. Japan is currently the only country with a national antenatal screening programme in place. HTLV-1 is primarily transmitted sexually in adulthood, however it can be transmitted from mother-to-child perinatally. This can occur transplacentally, during the birth process or via breastmilk. If HTLV-1 is transmitted perinatally then the lifetime risk of adult T cell leukemia/lymphoma rises from 5 to 20%, therefore prevention of mother-to-child transmission of HTLV-1 is a public health priority. There are reliable immunological and molecular tests available for HTLV-1 diagnosis during pregnancy and screening should be considered on a country by country basis. Further research on best management is needed particularly for pregnancies in women with high HTLV-1 viral load. A first step would be to establish an international registry of cases and to monitor outcomes for neonates and mothers. We have summarized key risk factors for mother-to-child transmission of HTLV-1 and subsequently propose a pragmatic guideline for management of mothers and infants in pregnancy and the perinatal period to reduce the risk of transmission. This is clinically relevant in order to reduce mother-to-child transmission of HTLV-1 and it's complications.

Abstract Adult T cell leukaemia/lymphoma (ATL) arises from clonally expanded T cells that are infected with human T cell leukaemia virus type-1 (HTLV-1). Here, we show that ATL can 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 the 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.

Abstract Introduction Chronic infection with human T‐cell lymphotropic virus type‐1 (HTLV‐1) may result in aggressive adult T‐cell leukaemia/lymphoma (ATL) in 4‐6% carriers. The majority of this risk arises in carriers infected during infancy, and so each infant has ∼25% lifetime risk. Other risk factors include a family history of ATL. Antenatal HTLV‐1 screening is not undertaken in the UK. Methods Here we describe four cases of ATL diagnosed during pregnancy and describe strategies to minimise HTLV‐1 transmission to neonates. Results/conclusion These cases highlight undiagnosed HTLV‐1 in pregnancy which allows ongoing mother to child vertical transmission and risk of future ATL. We recommend the UK National Screening Committee incorporate HTLV‐1 serology into antenatal screening.

Abstract The lung is one of several organs that can be affected by HTLV-1 mediated inflammation. Pulmonary inflammation associated with HTLV-1 infection involves the interstitium, airways and alveoli, resulting in several clinical entities including interstitial pneumonias, bronchiolitis and alveolitis, depending on which structures are most affected. Augmentation of the inflammatory effects of HTLV-1 infected lymphocytes by recruitment of other inflammatory cells in a positive feedback loop is likely to underlie the pathogenesis of HTLV-1 associated pulmonary disease, as has been proposed for HTLV-1 associated myelopathy. In contrast to the conclusions of early case series, HTLV-1 associated pulmonary disease can be associated with significant parenchymal damage, which may progress to bronchiectasis where this involves the airways. Based on our current understanding of HTLV-1 associated pulmonary disease, diagnostic criteria are proposed.

Abstract Background Urinary dysfunction is one of the main features of human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, a comprehensive assessment of the severity is difficult because a standardized assessment measure is unavailable. Therefore, this study aimed to develop a novel symptom score for the assessment of urinary dysfunction in HAM/TSP. We interviewed 449 patients with HAM/TSP using four internationally validated questionnaires for assessment of urinary symptoms (27 question items in total): the International Prostate Symptom Score; the International Consultation on Incontinence Questionnaire-Short Form; the Overactive Bladder Symptom Score; and the Nocturia Quality-of-Life questionnaire. We developed a symptom score based on the data of 322 patients who did not use urinary catheters by selecting question items from questionnaires focused on descriptive statistics, correlation analysis, and exploratory factor analysis. The score distribution, reliability, and validity of the developed score were evaluated. Results First, 16 questions related to quality of life, situations, or subjective assessment were omitted from the 27 questions. Exploratory factor analysis revealed that the remaining 11 questions pertained to three factors: frequent urination, urinary incontinence, and voiding symptoms. Three questions, which had similar questions with larger factor loading, were deleted. Finally, we selected eight question items for inclusion in the novel score. The score distribution exhibited no ceiling or floor effect. The Cronbach’s alpha (0.737) demonstrated reliable internal consistency. The new score comprised two subscales with acceptable factorial validity (inter-factor correlation coefficient, 0.322): storage symptoms (frequent urination plus urinary incontinence) and voiding symptoms. The correlation between each item and the subscales suggested acceptable construct validity. Conclusions We developed a novel score, the HAM/TSP-Bladder Dysfunction Symptom Score, and demonstrated its reliability and validity. The applicability of this score to patients using catheters should be examined in future research.

Abstract Background In pregnancy, reduction of HIV plasma viral load (pVL) for the prevention of vertical transmission is time-constrained. The study primary objective is to investigate factors associated with faster initial HIV RNA half-life decay when combination antiretroviral treatment (cART) is initiated in pregnancy. Methods This was a multicentre, retrospective, observational study, conducted in south England, United Kingdom, between August 2001 and February 2018. Data were extracted from case notes of eligible women initiating cART during the index pregnancy. Anonymised data were collated and analysed centrally. Regression analyses were conducted to determine factors associated with faster HIV RNA half-life decay in the first 14 days after commencing cART (first-phase), and with achieving an undetectable maternal pVL by 36 weeks’ gestation. We then assessed whether HIV- and obstetric- related parameters differed by antiretroviral third agent class and whether the proportions of women with undetectable pVL at 36 weeks’ gestation and at delivery differed by antiretroviral third agent class. Results Baseline pVL was the only independent factor associated with faster first-phase HIV RNA half-life decay on commencing cART. Lower pVL on day 14 after starting cART was associated with an increased likelihood of achieving an undetectable pVL by 36 weeks’ gestation. Integrase inhibitor-based cART was associated with a faster first-phase HIV RNA half-life decay on commencing cART. Overall, 73% and 85% of women had an undetectable pVL at 36 weeks’ gestation and at delivery respectively, with no significant difference by antiretroviral third agent class. Conclusions Only high baseline pVL independently contributed to a faster rate of first-phase viral half-life decay. pVL at 14 days after initiating cART allows early identification of treatment failure. In the first 14 days after initiating cART in pregnancy, integrase inhibitor-based cART reduced maternal pVL faster than protease inhibitor- and non-nucleoside reverse transcriptase-based cART. While our study findings support INSTI use when initiated in pregnancy especially when initiated at later gestations and in those with higher baseline pVL, other non-INSTI based cART with more data on safety in pregnancy also performed well.

ABSTRACTAfrica is the largest endemic area for HTLV-1, with many molecular genotypes. We previously demonstrated that some strains from North Africa (a-NA clade) originated from a recombinant event between Senegalese and West African strains. A series of 52 new HTLV-1 strains from 13 North and West African countries were sequenced in the LTR region and/or a env gene fragment. Four samples from French Guyanese of African origin were also added. Furthermore, 7 complete sequences from different genotypes were characterized. Phylogenetic analyses showed that most of the new African strains belong to the Cosmopolitan a-genotype. Ten new strains from the a-NA clade were found in Morocco, Western Sahara, Mali, Guinea, Côte d'Ivoire and Ghana. A new a-G-Rec clade, which arose from a distinct recombination event between Senegalese and West African strains, was identified in Guinea and Ghana. The complete sequences suggest that recombination occur in the LTR as well as the env/pol region of the genome, thus a-NA and a-G-Rec strains have a mosaic profile with genetic segments from either a-WA or a-Sen strains. Our work demonstrates that recombination in HTLV-1 may not be as rare an event as previously proposed.

Human T lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes lifelong T-cell infection in humans, impacting the host immune response. This virus causes a range of clinical manifestations, from inflammatory conditions, including neuronal damage (HTLV-1 associated myelopathy, HAM) to life-threatening leukemia (adult T-cell leukemia, ATL). Human T lymphotropic virus type 1 is also associated with increased risk of all-cause mortality, but the mechanisms remain unclear. As a blood-borne and sexually transmitted infection (STI), HTLV-1 shares transmission routes to many other pathogens and although it has worldwide distribution, it affects mainly those in low- and middle-income tropical areas, where the prevalence of other infectious agents is high. These factors contribute to a high incidence of co-infections in people living with HTLV-1 (PLHTLV). This comprehensive review addresses the impact of HTLV-1 on several co-infections and vice-versa. There is evidence of higher rates of HTLV-1 infection in association with other blood borne (HCV, HBV) and sexually transmitted (Syphilis, Chlamydia, HPV, HSV) infections but whether this represents increased susceptibility or opportunity is unclear. Higher frequency of Mycobacterium tuberculosis (MTb) and Mycobacterium leprae (M. leprae) is observed in PLHTLV. Reports of opportunistic infections and high frequency of crusted scabies in patients with HTLV-1 points to immune impairment in those individuals. Human T lymphotropic virus type 1 may influence the persistence of pathogens, exemplified by the higher rates of Schistosoma mansoni and Strongyloides stercoralis (St. stercoralis) treatment failure observed in PLHTLV. This retrovirus is also associated with increased tuberculosis (TB) severity with some evidence pointing to a deleterious impact on leprosy outcome as well. These findings are supported by immune alterations observed in those co-infected individuals. Although the role of HTLV-1 in HCV outcome is debatable, most data indicate that HTLV may negatively impact the clinical course of hepatitis C. Co-infections may also influence the risk of developing HTLV-1 associated disease, but data are still limited. The impact of HTLV-1 on the response to more common infections, might contribute to the increased mortality rate of HTLV-1. Large scale prospective controlled studies on the prevalence and impact of HTLV-1 in co-infections and vice-versa are needed. Human T lymphotropic virus type 1 impact in public health is broad. Measures to increase awareness and to prevent new infections are needed.

BackgroundThe distribution of human T cell lymphotropic virus type 1 (HTLV-1) overlaps with that of Strongyloides stercoralis. Strongyloides stercoralis infection has been reported to be impacted by co-infection with HTLV-1. Disseminated strongyloidiasis and hyperinfection syndrome, which are commonly fatal, are observed in HTLV-1 co-infected patients. Reduced efficacy of anti-strongyloidiasis treatment in HTLV-1 carriers has been reported. The aim of this meta-analysis and systematic review is to better understand the association between HTLV-1 and S. stercoralis infection.MethodsPubMed, Embase, MEDLINE, Global Health, Healthcare Management Information Consortium databases were searched. Studies regarding the prevalence of S. stercoralis, those evaluating the frequency of mild or severe strongyloidiasis, and treatment response in people living with and without HTLV-1 infection were included. Data were extracted and odds ratios were calculated. Random-effect meta-analysis was used to assess the pooled OR and 95% confidence intervals.ResultsFourteen studies were included after full-text reviewing of which seven described the prevalence of S. stercoralis and HTLV-1. The odds of S. stercoralis infection were higher in HTLV-1 carriers when compared with HTLV-1 seronegative subjects (OR 3.2 95%CI 1.7–6.2). A strong association was found between severe strongyloidiasis and HTLV-1 infection (OR 59.9, 95%CI 18.1–198). Co-infection with HTLV-1 was associated with a higher rate of strongyloidiasis treatment failure (OR 5.05, 95%CI 2.5–10.1).ConclusionStrongyloides stercoralis infection is more prevalent in people living with HTLV-1. Co-infected patients are more likely to develop severe presentation and to fail treatment. Screening for HTLV-1 and Strongyloides sp. should be routine when either is diagnosed.

BackgroundPregnant women living with HIV infection (PWLWH) have elevated rates of preterm birth (PTB) in which HIV and cART are implicated. PWLWH also have a high prevalence of adverse vaginal microbiota, which associate with genital tract inflammation. The mechanism underlying PTB in PWLWH is unknown. We present the first data in PWLWH on genital-tract matrix-metalloproteinase-9(MMP-9), an important collagenase implicated in labour onset, and tissue inhibitor of metalloproteinases-1(TIMP-1) and explore correlations with local inflammation and vaginal bacteria.Material and MethodsCervical vaginal fluid (CVF) collected by a soft cup and high vaginal swabs (HVS) were obtained from PWLWH and HIV uninfected pregnant women (HUPW) at three antenatal time points. Maternal characteristics, combination antiretroviral therapy (cART) exposure, and pregnancy outcome were recorded. Concentrations of MMP-9, TIMP-1 and ten cytokines were measured by immunoassays. Vaginal microbiota composition was determined through 16S rRNA amplicon sequencing. MMP-9, TIMP-1 and cytokine concentrations were compared by HIV status, cART, and prematurity and in PWLWH correlations with polymorphonuclear leucocytes, cytokines and bacterial genera were explored.ResultsCVF was available for 50 PWLWH (108 samples) and 12 HUPW (20 samples) between gestation weeks 14-38. Thirty-six PWLWH conceived on cART and 14 initiated post-conception. There were five and one PTB outcomes in PWLWH and HUPW respectively. PWLWH had higher mean CVF concentrations of MMP-9 (p

Human T lymphotropic virus 1 (HTLV-1) may be transmitted from mother to child and affects at least 5–10 million individuals worldwide, with severe consequences on health. Strategies to prevent transmission are important, as there is no treatment or vaccine. This systematic review aimed to identify interventions to prevent HTLV-1 mother-to-child transmission and to determine their effectiveness. Exclusive formula feeding, short-term breastfeeding, use of freeze–thaw milk, milk pasteurization, maternal and infant antiretroviral drugs, caesarean section, early clamping of umbilical cord, screening of milk donors and avoidance of cross-breastfeeding were identified as possible strategies. Avoidance of breastfeeding is an intervention that prevents 85% of transmissions. This strategy is recommended in Japan, Brazil, Colombia, Canada, Chile, Uruguay, the USA and some regions of French Guyana. Whilst breastfeeding for

Summary: We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.

BackgroundPregnant women living with HIV-1 infection (PWLWH) have an elevated risk of preterm birth (PTB) of unknown aetiology, which remains after successful suppression of HIV. Women at high risk for HIV have a common bacterial profile which has been associated with poor birth outcomes. We set out to explore factors associated with gestational age at delivery of PWLWH in a UK population.MethodsProspective study of PWLWH (n = 53) in whom the vaginal microbiota and cervicovaginal cytokine milieu were assessed using metataxonomics and multiplexed immunoassays, respectively. Cross-sectional characterisation of vaginal microbiota in PWLWH were compared with 22 HIV uninfected pregnant women (HUPW) at a similar second trimester timepoint. Within PWLWH the relationships between bacterial composition, inflammatory response, and gestational age at delivery were explored.FindingsThere was a high rate of PTB among PWLWH (12%). In the second trimester the vaginal microbiota was more diverse in PWLWH than in HUPW (Inverse Simpson Index, p = 0.0004 and Species Observed, p = 0.009). PWLWH had a lower prevalence of L. crispatus dominant vaginal microbiota group (VMB I, 15 vs 54%) than HUPW and higher prevalence of L. iners dominant (VMB III, 36 vs 9% and VMB IIIB, 15 vs 5%) and mixed anaerobes (VMB IV, 21 vs 0%). Across the second and third trimesters in PWLWH, VMB III/IIIB and IV were associated with PTB and with increased local inflammation [cervicovaginal fluid (CVF) cytokine concentrations in upper quartile]. High bacterial diversity and anaerobic bacterial abundance were also associated with CVF pro-inflammatory cytokines, most notably IL-1β.InterpretationThere is an association between local inflammation, vaginal dysbiosis and PTB in PWLWH. Understanding the potential of antiretroviral therapies to influence this cascade will be important to improve birth outcomes in this population.

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were −13.8% (95% CI: −20.1–−7.1; p < 0.001) and −6.0% (95% CI: −12.8–1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085)

Abstract 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.

We report human T-cell lymphotropic virus type 1 infection associated with self-flagellation in 10 UK residents. These persons were heterosexual men from Pakistan, India, and Iraq. One person showed seroconversion in adulthood; 1 was co-infected with hepatitis C virus. No other risk factors for bloodborne virus acquisition were identified. Onward sexual transmission has occurred.

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.

We are pleased to report on the inaugural HTLV-1 symposium at the 2017 Australasian HIV and AIDS Conference joint with 2017 Australasian Sexual Health Conference in Canberra, Australia. Our understanding of HTLV-1 epidemiology, pathogenesis, laboratory diagnostics and treatment options for HTLV-1 diseases has advanced tremendously over the last 40 years. However, the awareness of healthcare providers and the general population about HTLV-1, and the effective promotion and implementation of HTLV-1 transmission-prevention strategies, lag behind current knowledge. Here we present a summary of the symposium, plenary and poster presentations on HTLV-1.

Mogamulizumab, a humanized defucosylated anti-C-C chemokine receptor 4 monoclonal antibody, has been approved in Japan for the treatment of C-C chemokine receptor 4-positive adult T-cell leukemia/lymphoma (ATL). This phase II study evaluated efficacy and safety of mogamulizumab in ATL patients with acute, lymphoma, and chronic subtypes with relapsed/refractory, aggressive disease in the US, Europe, and Latin America. With stratification by subtype, patients were randomized 2:1 to intravenous mogamulizumab 1.0 mg/kg once weekly for 4 weeks and biweekly thereafter (n=47) or investigator’s choice of chemotherapy (n=24). The primary end point was confirmed overall response rate (cORR) confirmed on a subsequent assessment at 8 weeks by blinded independent review. ORR was 11% (95%CI: 4-23%) and 0% (95%CI: 0-14%) in the mogamulizumab and chemotherapy arms, respectively. Best response was 28% and 8% in the respective arms. The observed hazard ratio for progression-free survival was 0.71 (95%CI: 0.41-1.21) and, after post hoc adjustment for performance status imbalance, 0.57 (95%CI: 0.337-0.983). The most frequent treatment-related adverse (grade ≥3) events with mogamulizumab were infusion-related reaction and thrombocytopenia (each 9%). Relapsed/refractory ATL is an aggressive, poor prognosis disease with a high unmet need. Investigator’s choice chemotherapy did not result in tumor response in this trial; however, mogamulizumab treatment resulted in 11% cORR, with a tolerable safety profile.

Mother-to-child transmission (MTCT) of Human T-cell lymphotropic virus type 1 (HTLV-1) causes lifelong infection. At least 5–10 million individuals worldwide are currently living with HTLV-1. Studies of regional variation are required to better understand the contribution of MTCT to the global burden of infection. Although most infected individuals remain asymptomatic ∼10% develop high morbidity, high mortality disease. Infection early in life is associated with a higher risk of disease development. Adult T-cell leukemia (ATL), which is caused by HTLV-1 and has a median survival of 8 months is linked to MTCT, indeed evidence of ATL following infection as an adult is sparse. Infective dermatitis also only occurs following neonatal infection. Whilst HTLV-1-associated myelopathy (HAM) follows sexual and iatrogenic infection approximately 30% of patients presenting with HAM/TSP acquired the infection through their mothers. HAM/TSP is a disabling neurodegenerative disease that greatly impact patient’s quality of life. To date there is no cure for HTLV-1 infection other than bone marrow transplantation for ATL nor any measure to prevent HTLV-1 associated diseases in an infected individual. In this context, prevention of MTCT is expected to contribute disproportionately to reducing both the incidence of HTLV-1 and the burden of HTLV-1 associated diseases. In order to successfully avoid HTLV-1 MTCT, it is important to understand all the variables involved in this route of infection. Questions remain regarding frequency and risk factors for in utero peri-partum transmission whilst little is known about the efficacy of pre-labor cesarean section to reduce these infections. Understanding the contribution of peripartum infection to the burden of disease will be important to gauge the risk-benefit of interventions in this area. Few studies have examined the impact of HTLV-1 infection on fertility or pregnancy outcomes nor the susceptibility of the mother to infection during pregnancy and lactation. Whilst breast-feeding is strongly associated with transmission and avoidance of breast-feeding a proven intervention little is known about the mechanism of transmission from the breast milk to the infant and there have been no clinical trials of antiretroviral therapy (ARV) to prevent this route of transmission.

An amendment to this paper has been published and can be accessed via the original article.

Outbreaks of serious infections associated with heroin use in persons who inject drugs (PWIDs) occur intermittently and require vigilance and rapid reporting of individual cases. Here, we give a firsthand account of the cases in London during an outbreak of heroin-associated anthrax during 2009–2010 in the United Kingdom. This new manifestation of anthrax has resulted in a clinical manifestation distinct from already recognized forms. During 2012–13, additional cases of heroin-associated anthrax among PWIDs in England and other European countries were reported, suggesting that anthrax-contaminated heroin remains in circulation. Antibacterial drugs used for serious soft tissue infection are effective against anthrax, which may lead to substantial underrecognition of this novel illness. The outbreak in London provides a strong case for ongoing vigilance and the use of serologic testing in diagnosis and serologic surveillance schemes to determine and monitor the prevalence of anthrax exposure in the PWID community.

OBJECTIVE: Tropical Spastic Paraparesis/HTLV-I Associated Myelopathy (TSP/HAM) is a chronic myelopathy, and pain has been mentioned as a frequent sensory symptom in this condition. The authors aimed at analyzing this symptom in a TSP/HAM patients series. METHOD: For this, 46 patients were analyzed considering demographic and clinical characteristics and complaint of pain as to verbal description, time of onset and classification, correlated with the degree of motor disability and type of pain. RESULTS: Among the 46 TSP/HAM patients, 28 (60.8%) complained of pain, predominant in the early phase of the disease. Most of the patients exhibited neuropathic characteristics of pain, correlated with increased motor disability. CONCLUSION: Pain in TSP/HAM patients is a frequent and early symptom, and the neuropathic type is predominant (57.1%) and paralleled with increased incapacitation. The pathogenic involvement of cytokines may possibly be involved in the meaning of this symptom in this condition.OBJETIVO: A Paraparesia Espástica Tropical/Mielopatia Associada ao HTLV-I (PET/MAH) é uma mielopatia crônica, e a dor tem sido mencionada como um sintoma sensitivo freqüente nessa condição. Os autores objetivam analisar esse sintoma numa série de pacientes com PET/MAH. MÉTODO: Para isso, 46 pacientes foram analisados considerando características demográficas e clínicas, e queixa de dor do ponto de vista da descrição verbal, tempo de início e classificação, correlacionados com o grau de incapacitação motora e o tipo de dor. RESULTADOS: Dentre os 46 pacientes com PET/MAH, 28 (60,8%) se queixavam de dor, predominando na fase inicial da doença. A maioria dos pacientes evidenciou características de dor neuropática, correlacionada com aumento da incapacitação motora. CONCLUSÃO: A dor em pacientes com PET/MAH é um sintoma freqüente e inicial, sendo o tipo neuropático predominante (57,1%) e em paralelo com maior incapacitação. O envolvimento patogênico das citocinas poderá possivelmente estar relacionado com o significado desse sintoma nessa condição clínica.

Out of 153 newly referred human T-lymphotropic virus type I infected patients, 42 (27%) had 5% or more abnormal lymphocytes, consistent with the diagnosis of smoldering adult T-cell leukemia/lymphoma. The abnormal lymphocyte percentage was higher in patients with human T-lymphotropic virus type I associated inflammatory disease compared with asymptomatic carriers (P=0.006). Over 4.5 years median follow up, 4 patients, all with 10 or more human T-lymphotropic virus type I DNA copies/100 peripheral blood mononuclear cells at presentation, but only one with 5% or more abnormal lymphocytes at presentation, developed adult T-cell leukemia/lymphoma. Thus, high pre-morbid human T-lymphotropic virus type I proviral load, rather than fulfilment of the classification criteria for smoldering adult T-cell leukemia/lymphoma, was associated with an increased risk of developing aggressive adult T-cell leukemia/lymphoma.