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Intravenous immunoglobulin (IVIg) has been increasingly used to treat immunodeficiencies and inflammatory disorders. However, IVIg has also been shown to affect a wide range of laboratory testing, including human T-lymphotropic virus (HTLV) screening. Our laboratory frequently observes false reactive HTLV screens from patients receiving IVIg infusions, however the extent of IVIg contribution to the false reactivity has not been extensively investigated. The objective of this study was to explore the prevalence of HTLV-1/2 infection in patients from the Sydney metropolitan area and evaluate the positive predictive value for HTLV screening test in sera from patients with or without IVIg infusions. HTLV screening test results from sera of 3843 patients referred to Central Sydney Immunology Laboratory between June 2006 and May 2021 were retrospectively analysed. Among 72 (1.9%) sera reactive on screening enzyme-linked immunosorbent assay (ELISA), 62 (86.1%) were from patients receiving IVIg infusions, including 60 collected post-IVIg and two collected pre-IVIg infusions. Only two (3.3%) of the 60 post-IVIg sera were positive on confirmatory western blot. In contrast, in non-IVIg sera, five (50.0%) from the 10 screen-reactive sera were positive on western blot. If positive western blot is used as the reference for determining 'true' HTLV infection, we found the positive predictive value of HTLV screening ELISA in sera collected post-IVIg (3.3%) is considerably lower than that in non-IVIg and pre-IVIg sera (41.7%). The vast majority of false reactive screen results (89.2%) in our study cohort were from sera collected post-IVIg infusion. Our study suggests that the high incidence of falsely reactive results in HTLV screening ELISA could be attributed to IVIg infusion. Hence, collection of sera from patients on IVIg should be avoided and screen-reactive results should be interpreted with greater caution, particularly for patients from non-endemic areas.

To investigate a 12-year historical series (2006-2017) of human T-cell lymphotropic virus (HTLV)-positive blood donations from Fundação Hemominas, Minas Gerais, Brazil, an observational retrospective study was performed to evaluate data of blood donor candidates who were screened for HTLV-1/2 by enzyme-linked immunosorbent assay or chemiluminescence assays and confirmed by Western blot. We analyzed 3 309 716 blood donations covering 2006-2017 that were extracted from the institutional database. In a total of 3 308 738 donations that have complete algorithm tests, the global frequency of HTLV-positive donations was 0.012%. The seroprevalence in first-time blood donors was 28.82/100 000 donors; 0.95/100 000 donations were HTLV-positive in repeat blood donors. The frequency of HTLV-seropositive females was significantly higher than males (odds ratio = 1.85, p 0.001) in first-time donors. The median age of HTLV-positive first-time and repeat donors was similar (36 and 32 years, respectively). First-time donors ≥41 years had higher odds to be infected. There was a clear tendency of decline in the HTLV-positive donations in the period analyzed, going from 19.26/100 000 donations to 8.50/100 000 donations. The increase in the proportion of repeat donors over the period analyzed (from 23% in 2006 to 67% in 2017) must be the principal factor that contributed to this drop. Our results showed a continuous decline in the frequency of HTLV-positive donations from Minas Gerais, Brazil throughout 12 years and emphasize the importance of having a high rate of repeat donors in blood centers to reduce the residual risk of transfusion-transmitted infections.

A risk-based approach to the testing of blood donations for Human T-Lymphotropic Virus (HTLV) should include an assessment of blood donation seroepidemiology. The objectives of the present study were to determine the proportion of HTLV positive units in Irish blood donations, and subsequently, to estimate the current risk of transfusion transmitted HTLV (TT-HTLV).Over 3 million donations screened between 1996 and 2020, were included in the study (n = 3,666,253). Factors considered in the assessment of TT-HTLV risk included: (I) HTLV seropositivity, (ii) probability of a leucodepletion failure, and (iii) the HTLV testing strategy.Six HTLV positive donations were detected throughout the study period, all of them in previously unscreened blood donors (0.000164%; n = 6/3,666,253), 3 of whom had donated prior to the introduction of HLTV antibody testing. On average 0.11% of manufactured blood components assessed, failed to satisfy the leucodepletion quality assurance criteria of less than 1 × 10This is the first report on the proportion of HTLV positive in Irish blood donations (1996-2020) and will be used to inform blood donation screening policy in Ireland. Evidence is provided for recommending a selective HTLV donor screening algorithm in Ireland that is accompanied by a robust framework for continued surveillance of leucodepletion failure rate.

Transfusion-transmitted viruses count among the greatest threats to blood safety. In Argentina, current laws oblige testing all donated blood for the presence of antibodies against human T-cell lymphotropic viruses 1 and 2 (HTLV-1/2). In endemic zones of the country, a high rate of seronegative HTLV-1 individuals with clear evidence of infection because of symptoms and/or presence of tax sequences of HTLV-1 and/or IgG anti-Tax antibodies has been recently described. Migration from endemic to nonendemic zones of Argentina is very frequent.During a 1-year period, in the blood bank of Córdoba city, we performed molecular screening of all donors who were born in or arose from endemic zones for HTLV-1/2 in Argentina and neighbouring countries.By screening 219 bp of HTLV-1/2 tax gene, 0.6% (2/317) of the blood donors proved to be positive for HTLV-1 tax sequence. One of the donors presented anti-Tax antibodies, demonstrating the transcriptional activity of the tax gene, and the other donor was also positive for LTR and pol gene sequences. The HTLV-1 genetic analysis of the LTR sequence determined that it belonged to the Cosmopolitan subtype HTLV-1aA.These findings suggest potential limitations of some currently approved screening assays for HTLV-1 detection applied in some donor populations and the possibility of an HTLV-1 seronegative carrier state with the potential for silent transmission by blood.

Japan is one of the world's highly endemic areas for human T cell leukemia virus type 1 (HTLV-1), and it is known that the infection rate of HTLV-1 increases with age. The infection rate among the elderly has been estimated based on data from blood donors under the age of 65, and the actual number and rate of infection among the elderly are unknown. Data of 26,090 preoperative HTLV-1 screening tests conducted at Kagoshima University Hospital from 2001 to 2020, including 2726 HTLV-1-positive patients, were used for calculating the decadal infection rates for the year of birth. Estimated infection rates by birth year and demographic tables were used to estimate the current number of infected people in Kagoshima. The estimated total numbers of people infected with HTLV-1 in Kagoshima prefecture were 139,436 in 2005 and 80,975 in 2019. The infection rate increased with age for both men and women, reaching 17.3% for women born before the 1920s. Next, we tried to clarify whether the increase in infection rates with age was due to post-school age infections. The age of birth with the greatest increase in infection rate after 10 years was women born in the 1970s, and the increase in infection rate was only 0.98%, which is not a statistically significant increase. The number of infected people in Kagoshima was80,000 in 2019. No data were available in this study to point to the involvement of horizontal transmission after school age in the high infection rate among the elderly. The high infection rate among the elderly is thought to have been high even when they were infants.

In the United Kingdom, organ donors/recipients are screened for evidence of human T-cell leukaemia virus type-1 and type-2 (HTLV-1/2) infections. Since the United Kingdom is a low prevalence country for HTLV infections, a screening assay with high sensitivity and specificity is required. Samples with repeat reactivity on antibody testing are sent to a reference lab for confirmatory serological and molecular testing. In the case of donor screen, this leads to delays in the release of organs and can result in wastage. We aim to assess whether a signal/cut-off (S/CO) ratio higher than the manufacturer's recommendation of 1.0 in the Abbott Architect antibody assay is a reliable measure of HTLV-1/2 infection.We conducted a 5 year retrospective analysis of 7245 patients from which 11 766 samples were tested on the Abbott Architect rHTLV I/II assay. Reactive samples (S/CO 1) were referred for confirmatory serological and molecular detection (Western Blot and proviral DNA) at UK Health Security Agency, (formerly PHE, Colindale), the national reference laboratory. Electronic, protected laboratory and hospital patient databases were employed to collate data.A total of 45 patients had initially reactive samples. 42.2% (n = 19/45) had an S/CO ratio 20, with HTLV infection confirmed in n = 18/19 and indeterminate confirmatory results in n = 1/19. No samples with an S/CO ratio4 (48.9%, n = 22/45) or 4-20 (8.9%, n = 4/45) had positive confirmatory results on subsequent confirmatory testing.Samples with an S/CO20 likely represent a true HTLV-1/2 infection. Reactive samples with an S/CO 4 were unlikely to confirm for HTLV infections. Interpretation of these ratios can assist clinicians in the assessment of low reactive samples and reiterates the need for faster access to confirmatory testing.

It is obvious that genetic differences, including mutations and polymorphisms, can play an important role in viral infections. In this case-control study, which included 81 human T-cell leukemia virus type 1 (HTLV-1) asymptomatic carriers (AC) and 162 healthy controls (HC), the rs4143815 polymorphism of PDL1 gene was investigated. This polymorphism is the site of miR-570 binding and it can influence immune system responses. The rs4143815 polymorphism was evaluated by allele-specific polymerase chain reaction (AS-PCR) and the proviral load levels by quantitative real-time PCR (q PCR). The results demonstrated that the C allele (P = 0.027) and the CC genotype (P = 0.031) of rs4143815 polymorphism was significantly higher in the AC group than in the HC group, also the proviral load in the AC group with the C allele (P = 0.020) was significantly higher. Thus, the rs4143815 polymorphism can play a vital role in HTLV-1 infection.

Human T-cell leukemia virus 1 (HTLV-1) causes adult T-cell leukemia (ATL), but the mechanism underlying its initiation remains elusive. In this study, ORP4L was expressed in ATL cells but not in normal T-cells. ORP4L ablation completely blocked T-cell leukemogenesis induced by the HTLV-1 oncoprotein Tax in mice, whereas engineering ORP4L expression in T-cells resulted in T-cell leukemia in mice, suggesting the oncogenic properties and prerequisite of ORP4L promote the initiation of T-cell leukemogenesis. For molecular insight, we found that loss of miR-31 caused by HTLV-1 induced ORP4L expression in T-cells. ORP4L interacts with PI3Kδ to promote PI(3,4,5)P3 generation, contributing to AKT hyperactivation; NF-κB–dependent, p53 inactivation-induced pro-oncogene expression; and T-cell leukemogenesis. Consistently, ORP4L ablation eliminates human ATL cells in patient-derived xenograft ATL models. These results reveal a plausible mechanism of T-cell deterioration by HTLV-1 that can be therapeutically targeted.

Background: The HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the most common neurological manifestation associated with Human T-cell Lymphotropic Virus type-1 (HTLV-1) infection. Although cognitive impairment has been highlighted in the spectrum of HTLV-1 neurological manifestations, it may go unnoticed in those who do not spontaneously report it. We aimed at evaluating the applicability of a self-perceived memory score (SMS) and the cognitive event-related potential (P300) for the early detection of cognitive impairment in HTLV-1-infected people. Methods: The SMS was measured by a 0-10 visual analog scale combined with a sad-happy faces rating scale. The higher the number, the better was the SMS. The P300 was obtained through an oddball paradigm with a mental counting task. The participants were 15(21,4%) individuals with HAM/TSP, 20(28,6%) HTLV-1-asymptomatic carriers, and 35(50%) seronegative controls. Results: SMS (p369.0 milliseconds were considered as altered result and indicated cognitive impairment. The HAM/TSP group showed the highest prevalence of altered P300 (80%) and SMS (87%). Interestingly, the asymptomatic group also presented significant higher prevalence of altered SMS (60%) and P300 (35%) when compared to controls (Conclusion: The use of SMS in the medical consultation was a useful and easy-to-apply method to screen HTLV-1 infected subjects for everyday memory complaints.

Proviral load (PVL) is one of the determining factors for the pathogenesis and clinical progression of the human T-lymphotropic virus type I (HTLV-1) infection. In the present study, we optimized a sensitive multiplex real-time PCR for the simultaneous detection and quantification of HTLV-1 proviral load and beta-globin gene as endogenous control. The values obtained for HTLV-1 PVL were used to monitor the clinical evolution in HTLV-1-infected individuals. A vector containing cloned DNA targets of the real-time PCR for the beta-globin gene and the HTLV-1pol region was constructed. For the reaction validation, we compared the amplification efficiency of the constructed vector and MT-2 cell line containing HTLV-1. The analytical sensitivity of the reaction was evaluated by the application of a standard curve with a high order of magnitude. PVL assay was evaluated on DNA samples of HTLV-1 seropositive individuals. The construct showed adequate amplification for the beta-globin and HTLV-1 pol genes when evaluated as multiplex real-time PCR (slope = 3.23/3.26, Y-intercept = 40.18/40.73, correlation coefficient r

Introduction: Human T-lymphotropic virus (HTLV) 1 and 2 infections can lead to neurological diseases, mainly in HIV/HTLV 1 coinfected. Furthermore, HTLV 1 infection in HIV/AIDS patients has also been associated with AIDS progression. Despite this, HTLV 1/2 infections are not of mandatory notification in Brazil. Here, we describe the prevalence of HTLV 1/2 in HIV/AIDS patients from Paraíba state, Brazil, as well as the sociodemographic characteristics of the coinfected individuals. Methodology: Information about HIV viral load and TCD4 lymphocyte count were obtained from patients’ records. Data on the patients’ sociodemographic characteristics were obtained by interview conducted after signing the informed consent form. The serological diagnosis for HTLV 1/2 was performed by Enzyme-Linked Immunosorbent Assay (ELISA) and Western Blot (WB). Results: A total of 401 HIV/AIDS patients participated in the study, of whom about 1.5% (6/401) were positive for antibodies against HTLV, specifically for HTLV 1, evaluated by both ELISA and WB. No risk factors were found associated with HIV/HTLV 1/2 coinfection. Conclusions: We report a 1.5% prevalence of HTLV 1 infection in HIV/AIDS patients from Paraíba state. Although we have not identified risk factors associated with HTLV 1, we describe the most observed sociodemographic characteristics in HIV/HTLV 1 coinfection.

Immunomodulatory imide drugs (IMiDs), such as lenalidomide and pomalidomide, exert pleiotropic effects, e.g., antitumor effects in multiple myeloma, by binding the protein Cereblon and altering its substrate specificity. Lenalidomide is approved for the treatment of adult T-cell leukemia/lymphoma (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1), although the precise mechanisms responsible for its effectiveness have not been fully elucidated. Here, we used HTLV-1-infected cell lines to investigate how IMiDs exert anti-ATL effects. In three of four tested HTLV-1-infected cell lines, the cells treated with lenalidomide or pomalidomide exhibited mild growth suppression without apoptosis, which was associated with decreased IRF4, c-Myc, and phosphorylated STAT3 levels as well as enhanced SOCS3 expression. Additionally, the levels of enhancer of zeste homolog 2 (EZH2) and trimethyl histone 3 Lys27 (H3K27me3) were decreased following IMiD treatment in all three susceptible cell lines. An IMiD-mediated reduction of EZH2 and H3K27me3 levels was also observed in a multiple myeloma cell line. Furthermore, treatment with an EZH2-inhibitor reproduced the IMiD-mediated effects in HTLV-1-infected cells and multiple myeloma cells. These findings strongly suggest that a reduction of EZH2 expression is involved in the mechanism underlying the antitumor effects of IMiD.

Background: Although the burden of bronchiectasis is recognized globally, pediatric data are limited, particularly on trends over the years. Also, no published data exists regarding whether vitamin D deficiency or insufficiency and human T-cell lymphotropic virus type 1 (HTLV-1) infection, both found to be related to severe bronchiectasis in First Nations adults, also are important in children with bronchiectasis. Research Question: Among children with bronchiectasis, (1) have the clinical and BAL profiles changed between two 5-year periods (period 1, 2007-2011; period 2, 2012-2016) and (b) are vitamin D deficiency or insufficiency, HTLV-1 infection, or both associated with radiologic severity of bronchiectasis? Study Design and Methods: We analyzed the data from children with bronchiectasis prospectively enrolled at Royal Darwin Hospital, Australia, at the first diagnosis; that is, no child was included in both periods. Data collected include demographics, BAL, routine investigation bloods, and high-resolution CT scan of the chest evaluated using the Bhalla and modified Bhalla scores. Results: The median age of the 299 children was 2.2 years (interquartile range, 1.5-3.7 years). One hundred sixty-eight (56%) were male and most were First Nations (92%). Overall, bronchiectasis was high over time, particularly among First Nations children. In the later period, numbers of non-First Nations children more than tripled, but did not reach statistical significance. In period 2 compared with period 1, fewer First Nations children demonstrated chronic cough (period 1, 61%; period 2, 47%; P =.03), and were younger, First Nations children were less likely to have received azithromycin (period 1, 42%; period 2, 21%; P

Background HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors. Patients and methods We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification. Results We found that systemic IL-6 was positively correlated with both age (r = 0.50, p r = 0.45, p = 0.00049) in asymptomatics, revealing an ‘inflammaging” signature which was absent in HAM/TSP. GlycA levels were higher in women (p = 0.0069), but cytokine levels did not differ between the sexes. IFN-γ (p = 0.007) and IL-17A (p = 0.0001) levels were increased in untreated HAM/TSP Multivariable logistic regression identified IL-17A and proviral load as independent determinants of clinical status, resulting in modest accuracy of predicting HAM/TSP status (64.1%), while a machine learning-derived decision tree classified HAM/TSP patients with 90.7% accuracy. Pre-treatment GlycA and TNF levels significantly predicted clinical worsening (measured by Osame Motor Disability Scale), independent of proviral load. In addition, a poor prednisolone response was significantly correlated with higher post-treatment IFN-γ levels. Likewise, a transcriptomic IFN signaling score, significantly correlated with previously proposed HAM/TSP biomarkers (CASP5/CXCL10/FCGR1A/STAT1), was efficiently blunted by in vitro prednisolone treatment of PBMC from PLHTLV-1 and incident HAM/TSP. Conclusions An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLHTLV-1, in the absence of neurological disease. IFN-γ and IL-17A are biomarkers of untreated HAM/TSP, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy, paving the way for a precision medicine approach in HAM/TSP.

Neoplastic programmed cell death ligand 1 (PD-L1) expression, activated by PD-L1 gene alterations, is strongly associated with classic Hodgkin lymphoma (CHL). This association enabled a diagnostic consensus for lymphocyte-depleted CHL (LD-CHL), a previously enigmatic disease. We describe two patients with LD-CHL and primary extranodal disease. One patient was a 92-year-old female (Case #1) with a large mass that involved the uterus combined with swollen lymph nodes in the pelvic cavity. The second patient was a 76-year-old female (Case #2) with human T-cell leukemia virus type 1 (HTLV-1) who initially exhibited massive bone marrow involvement without peripheral lymphadenopathies. Biopsies of these tumors from the cervix uteri and bone marrow, respectively, revealed lesions rich in Hodgkin and Reed-Sternberg (H-RS) cells and diminished populations of other cell populations. Immunohistochemistry demonstrated that these H-RS cells expressed CD30, BOB1, and fascin, but not CD15, CD20, PAX5, or OCT2. They also expressed PD-L1, which led to our preferred diagnosis of LD-CHL in both patients. Epstein-Barr virus was associated with LD-CHL in Case #1, but not in Case #2. Both patients were deemed too frail for treatment. They died of disease at 1 (Case #1) and 15 months (Case #2) after the diagnosis. These findings highlight the abnormal biological behavior of this immune-escape-related lymphoid neoplasm in patients with immunodeficiency due to immune senescence and HTLV1 infection.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease that leads to motor impairment due to a chronic inflammatory process in the central nervous system (CNS). However, the HAM/TSP pathogenesis is not completely clear, and biomarkers to define the disease prognosis are still necessary. Thus, we aimed to identify biomarkers for HAM/TSP and potential mechanisms involved in disease development. To that end, the concentrations of VILIP-1, BDNF, VEGF, β-NGF, TGF-β1, fractalkine/CX3CL1, IL-6, IL-18, and TNF-α, and the soluble forms of TREM-1, TREM-2, and RAGE, were assessed using a multiplex bead-based immunoassay in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n = 20), asymptomatic HTLV-1 carriers (AC) (n = 13), and HTLV-1-seronegative individuals (n = 9), with the results analyzed according to the speed of HAM/TSP progression. HAM/TSP patients had elevated fractalkine in the serum but not in the CSF, particularly those with low neuroinflammatory activity (CSF/serum ratio of neopterin

Human T-cell leukemia virus type-1 (HTLV-1) establishes a long-term persistent infection in humans and causes malignant T-cell leukemia, adult T-cell leukemia (ATL). HTLV-1-specific cytotoxic T lymphocytes have been suggested to play a major role in the immunosurveillance of HTLV-1-infected T cells. However, it remains unclear whether HTLV-1-specific functional antibodies are also involved in the host defense. To explore the role of antibodies in the course of HTLV-1 infection, we quantitated HTLV-1-specific neutralizing and antibody-dependent cellular cytotoxicity (ADCC)-inducing antibody levels in plasma from asymptomatic carriers (ACs) and ATL patients. The levels of neutralizing antibodies, as determined by a syncytium inhibition assay, were significantly lower in acute and chronic ATL patients than in ACs. The levels of ADCC-inducing activity were tested using an autologous pair of HTLV-1-producing cells and cultured natural killer (NK) cells, which showed that the ADCC-inducing activity of IgG at a concentration of 100 µg/ml was comparable between ACs and acute ATL patients. The anti-gp46 antibody IgG levels, determined by ELISA, correlated with those of the neutralizing and ADCC-inducing antibodies. In contrast, the proviral loads did not correlate with any of these antibody levels. NK cells and a monoclonal anti-gp46 antibody reduced the number of HTLV-1 Tax-expressing cells in cultured peripheral blood mononuclear cells from patients with aggressive ATL. These results suggest a protective role for HTLV-1 neutralizing and ADCC-inducing antibodies during the course of HTLV-1 infection.

HTLV-1 is a global infection with 5-20 million infected individuals. Although only a minority of infected individuals develop myelopathy, lymphoproliferative malignancy, or inflammatory disorders, infection is associated with immunosuppression and shorter survival. Transmission of HTLV-1 is through contaminated blood or needles, mother-to-child exposure through breast-feeding, and sexual intercourse. HTLV-1 is a delta retrovirus that expresses immunogenic Gag, Envelope, TAX, and Hbz proteins. Neutralizing antibodies have been identified directed against the surface envelope protein, and cytotoxic T-cell epitopes within TAX have been characterized. Thus far, there have been few investigations of vaccines directed against each of these proteins, with limited responses, thus far. However, with new technologies developed in the last few years, a renewed investigation is warranted in search for a safe and effective HTLV-1 vaccine.

Spain; Screening; Transfusion España; Cribado; Transfusión Espanya; Cribratge; Transfusió Human T-cell lymphotropic virus type 1 and 2 (HTLV-1/2) screening is not mandatory in Spanish blood banks. In Catalonia, selective screening was introduced in 2008, followed by universal screening in 2011. We present herein a 10-year experience of HTLV testing in blood donors. HTLV-1/2 selective screening was performed using Ortho-Clinical Diagnostics HTLV-I/HTLV-II Ab-Capture ELISA between February 2008 and May 2009, then Abbott Prism HTLV-I/ HTLV-II assay until December 2010. Abbott Architect rHTLV-I/II assay was then used for HTLV-1/2 universal screening in pooled samples. INNO-LIA HTLV I/II Score (Fujirebio) and in-house HTLV-1/2 proviral DNA real-time PCR were used in reactive samples. Follow-up was offered to confirm HTLV-1/2 donors in Vall d’Hebron Hospital. Between 2008 and 2017, 51 blood donors were confirmed HTLV positive (46 HTLV-1, 4 HTLV-2 and 1 HTLV) out of 2,114,891 blood donations (1 in 41,468). Sixty-nine percent were female, median age was 40 years and most were born in Latin America (69%), followed by Europe (25%), Africa (4%) and Asia (2%). Screening of relatives and partners identified 12 additional HTLV-1 cases. Lookback studies did not show any HTLV-1/2 transmission. HTLV infections found in blood donors mirror epidemiological changes in the population of Spain. Consequently, HTLV should be considered a potential risk for recipients and calls for the design of optimal strategies to ensure transfusion safety. A.S.-M was supported by a postdoctoral grant “Juan Rodés” (JE18/00022) from the Instituto de Salud Carlos III through the Spanish Ministry of Economy and Competitiveness.

Human T-lymphotropic virus 1 (HTLV-1) infection causes two serious diseases: adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). Immunological studies have revealed that HTLV-1 Tax-specific CD8+cytotoxic T-cells (Tax-CTLs) in asymptomatic carriers (ACs) and ATL patients play an important role in the elimination of HTLV-1-infected host cells, whereas Tax-CTLs in HAM patients trigger an excessive immune response against HTLV-1-infected host cells infiltrating the central nervous system (CNS), leading to local inflammation. Our previous evaluation of HTLV-1 Tax301-309(SFHSLHLLF)-specific Tax-CTLs (Tax301-309-CTLs) revealed that a unique T-cell receptor (TCR) containing amino acid (AA)-sequence motif PDR, was shared among HLA-A*24:02+ACs and ATL patients and behaved as an eliminator by strong activity against HTLV-1. However, it remains unclear whether PDR+Tax301-309-CTLs also exist in HLA-A*24:02+HAM patients and are involved in the pathogenesis of HAM. In the present study, by high-throughput TCR repertoire analysis technology, we revealed TCR repertoires of Tax301-309-CTLs in peripheral blood (PB) of HLA-A*24:02+HAM patients were skewed, and a unique TCR-motif PDR was conserved in HAM patients (10 of 11 cases). The remaining case dominantly expressed (-DR, P-R, and PD-), which differed by one AA from PDR. Overall, TCRs with unique AA-sequence motifs PDR, or (-DR, P-R, and PD-) accounted for a total of 0.3-98.1% of Tax301-309-CTLs repertoires of HLA-A*24:02+HAM patients. Moreover, TCR repertoire analysis of T-cells in the cerebrospinal fluid (CSF) from four HAM patients demonstrated the possibility that PDR+Tax301-309-CTLs and (-DR, P-R, and PD-)+Tax301-309-CTLs efficiently migrated and accumulated in the CSF of HAM patients fostering increased inflammation, although we observed no clear significant correlation between the frequencies of them in PB and the levels of CSF neopterin, a known disease activity biomarker of HAM. Furthermore, to better understand the potential function of PDR+Tax301-309-CTLs, we performed immune profiling by single-cell RNA-sequencing of Tax301-309-CTLs, and the result showed that PDR+Tax301-309-CTLs up-regulated the gene expression of natural killer cell markerKLRB1(CD161), which may be associated with T-cell activation and highly cytotoxic potential of memory T-cells. These findings indicated that unique and shared PDR+Tax301-309-CTLs have a potential role in promoting local inflammation within the CNS of HAM patients.

Dendritic cells (DCs) function as a link between innate and adaptive immune responses. Retroviruses HIV-1 and HTLV-1 modulate DCs to their advantage and utilize them to propagate infection. Coinfection of HTLV-1 and HIV-1 has implications for cancer malignancies. Both viruses initially infect DCs and propagate the infection to CD4+ T cells through cell-to-cell transmission using mechanisms including the formation of virologic synapses, viral biofilms, and conduits. These retroviruses are both neurotrophic with neurovirulence determinants. The neuropathogenesis of HIV-1 and HTLV-1 results in neurodegenerative diseases such as HIV-associated neurocognitive disorders (HAND) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Infected DCs are known to traffic to the brain (CNS) and periphery (PNS, lymphatics) to induce neurodegeneration in HAND and HAM/TSP patients. Elevated levels of neuroinflammation have been correlated with cognitive decline and impairment of motor control performance. Current vaccinations and therapeutics for HIV-1 and HTLV-1 are assessed and can be applied to patients with HIV-1-associated cancers and adult T cell leukemia/lymphoma (ATL). These diseases caused by co-infections can result in both neurodegeneration and cancer. There are associations with cancer malignancies and HIV-1 and HTLV-1 as well as other human oncogenic viruses (EBV, HBV, HCV, HDV, and HPV). This review contains current knowledge on DC sensing of HIV-1 and HTLV-1 including DC-SIGN, Tat, Tax, and current viral therapies. An overview of DC interaction with oncogenic viruses including EBV, Hepatitis viruses, and HPV is also provided. Vaccines and therapeutics targeting host–pathogen interactions can provide a solution to co-infections, neurodegeneration, and cancer.

Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of the life-threatening diseases, adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy. Following implementation of antenatal screening in Japan, novel transmission of HTLV-1 in adolescent and adult generations is expected to replace vertical transmission as the main route for transmission.To obtain the current status of HTLV-1 horizontal infection and to assess the fluctuation of transmission occurring among adolescents and adults in Japan.We followed-up 5,017,916 eligible repeat blood donors for 8 years from 2013 to 2021. We evaluated HTLV-1 transmission rate by age group (16-69 years-old), and calculated the total number of novel transmissions in Japan using demographic statistics published by the government of Japan.We identified 457 seroconverters (men, 203; women, 254) in a total of 19,244,604 person-years during the study period. The number of seroconversions per 100,000 person-years was 1.54 for men and 4.21 for women. An increase in the number of novel infections was observed in both sexes in adolescent and young adult generations despite the health bias of blood donors.We estimate that more than 2,800 new HTLV-1 infections occur annually in Japan. It is a serious concern that without immediate measures against new HTLV-1 infections, such as guideline formulation, an inclusion of HTLV as routine screening in sexual health services, an information campaign, and surveillance of the general population, novel HTLV-1 infection could continue to increase in Japan and be a source of global transmission.

Mannose binding lectin-associated serine protease 2 (MASP2) is the effector part of mannose binding lectin (MBL) that activates the complement system in an antibody-independent manner. We aimed to investigate the role of genetic polymorphisms in the MASP2 gene and susceptibility to HTLV-1 infection. A total of 172 HTLV-1 infected individuals and 170 healthy blood donors were analyzed in this case-control study. Nine single nucleotide polymorphisms (SNPs) encompassing different regions of the MASP2 gene were genotyped with a polymerase chain reaction-sequence-specific primer (PCR-SSP) assay. The relation between the SNPs genotype and the susceptibility to HTLV-1 infection was investigated with a χ

The current study was conducted to examine the number of human T-cell leukemia virus type 1 (HTLV-1) carriers and how horizontal transmission affected the prevalence of HTLV-1 carriers among pregnant Japanese women in 2019. We requested 2,214 obstetrical facilities to provide information on HTLV-1 tests for pregnant women who delivered in 2019. The estimated number of HTLV-1 carriers among pregnant Japanese women was 952. At least 10% or more of the carriers acquired HTLV-1 through horizontal transmission.

Human T cell leukemia virus type 1 (HTLV-1), the etiological agent of adult T cell leukemia/lymphoma (ATLL) and of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), was identified a few years before Human Immunodeficiency Virus (HIV). However, forty years later, our comprehension of HTLV-1 immune detection and the host immune responses to HTLV-1 is far more limited than for HIV. In addition to innate and adaptive immune responses that rely on specialized cells of the immune system, host cells may also express a range of antiviral factors that inhibit viral replication at different stages of the cycle, in a cell-autonomous manner. Multiple antiviral factors allowing such an intrinsic immunity have been primarily and extensively described in the context HIV infection. Here, we provide an overview of whether known HIV restriction factors might act on HTLV-1 replication. Interestingly, many of them do not exert any antiviral activity against HTLV-1, and we discuss viral replication cycle specificities that could account for these differences. Finally, we highlight future research directions that could help to identify antiviral factors specific to HTLV-1.

Diagnosis; Myelopathy; Sexually transmitted infections Diagnóstico; Mielopatía; Infecciones de transmisión sexual Diagnòstic; Mielopatia; Infeccions de transmissió sexual Objectives Although only 10% of persons infected with human T-lymphotropic virus type 1 (HTLV-1) may develop virus-associated illnesses over their lifetime, missing the earlier diagnosis of asymptomatic carriers frequently leads to late presentation. Methods A nationwide HTLV-1 register was created in Spain in 1989. We examined the main demographics and clinical features at the time of the first diagnosis for more than three decades. Results A total of 428 individuals infected with HTLV-1 had been reported in Spain until the end of 2021. Up to 96 (22%) individuals presented clinically with HTLV-1-associated conditions, including subacute myelopathy (57%), T-cell lymphoma (34%), or Strongyloides stercoralis infestation (8%). Since 2008, HTLV-1 diagnosis has been made at blood banks (44%) or clinics (56%). Native Spaniards and Sub-Saharan Africans are overrepresented among patients presenting with HTLV-1-associated illnesses suggesting that poor epidemiological and/or clinical suspicion, which led to the late presentation are more frequent in them than carriers from Latin America (LATAM) (31.7% vs 20.4%, respectively; P = 0.015). Conclusion HTLV-1 infection in Spain is frequently diagnosed in patients presenting with characteristic illnesses. Although screening in blood banks mostly identifies asymptomatic carriers from LATAM, a disproportionately high number of Spaniards and Africans are diagnosed too late at the time of clinical manifestations. Expanding testing to all pregnant women and clinics for sexually transmitted infections could help to unveil HTLV-1 asymptomatic carriers. This work was supported in part by grants from FIS-ISCIII PI-21/1717 and Fundación Mutua Madrileña AP-174112020.

Genetic variations in components of the immune response seem to be an important factor that contributes to the manifestation of symptoms of some diseases related to HTLV-1 infection. Nerve growth factor (NGF) and the p75 neurotrophin receptor (p75

Adult T-cell leukemia (ATL) is a lymphoid neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), which encodes the transcriptional activator Tax, which participates in the immortalization of infected T cells. ATL is classified into 4 subtypes: smoldering, chronic, acute, and lymphoma. We determined whether natural killer receptors (NKRs) were expressed in ATL. NKR expression (KIR2DL1/2DS1, KIR2DL2/2DL3/2DS2, KIR3DL2, NKG2A, NKG2C, and NKp46) was assessed in a discovery cohort of 21 ATL, and KIR3DL2 was then assessed in 71 patients with ATL. KIR3DL2 was the only NKR among those studied frequently expressed by acute-type vs lymphoma- and chronic/smoldering-type ATL (36 of 40, 4 of 16, and 1 of 15, respectively; P = .001), although acute- and lymphoma-type ATL had similar mutation profiles by targeted exome sequencing. The correlation of KIR3DL2 expression with promoter demethylation was determined by microarray-based DNA methylation profiling. To explore the role of HTLV-1, KIR3DL2 and TAX messenger RNA (mRNA) expression levels were assessed by PrimeFlow RNA in primary ATL and in CD4+ T cells infected with HTLV-1 in vitro. TAX mRNA and KIR3DL2 protein expressions were correlated on ATL cells. HTLV-1 infection triggered KIR3DL2 by CD4+ cells but Tax alone did not induce KIR3DL2 expression. Ex vivo, autologous, antibody-dependent cell cytotoxicity using lacutamab, a first-in-class anti-KIR3DL2 humanized antibody, selectively killed KIR3DL2+ primary ATL cells ex vivo. To conclude, KIR3DL2 expression is associated with acute-type ATL. Transcription of KIR3DL2 may be triggered by HTLV-1 infection and correlates with hypomethylation of the promoter. The benefit of targeting KIR3DL2 with lacutamab is being further explored in a randomized phase 2 study in peripheral T-cell lymphoma, including ATL (registered on https://clinicaltrials.gov as #NCT04984837).