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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.

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.

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.

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.

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

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 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.

Central Australia is a human T cell leukaemia virus type 1c (HTLV-1c) endemic region which has the highest incidence of chronic kidney disease (CKD) in Australia. Factors associated with HTLV-1 seropositivity among Aboriginal Australian adults with CKD receiving haemodialysis (HD) were determined. A retrospective observational study of Aboriginal adults (≥ 18 years) who were receiving regular haemodialysis (HD) at the two main dialysis units in Alice Springs, 1st December 2010 to 31st December 2015. Demographic and clinical data prior to commencing HD were extracted from hospital records from first presentation to Alice Springs Hospital (ASH) to HD commencement and associations were determined using logistic regression. Among 373 patients receiving HD, 133 (35.9%) were HTLV-1 infected. Identifiable factors associated with HTLV-1 status included increasing age, male gender and diabetes prior to HD. The odds of diabetes mellitus was significantly higher among patients with HTLV-1 (aOR 2.76, 95% CI 1.19, 6.39; p=0.017). More than one fifth of participants had an acute kidney injury, the risk of which was increased among those with a previous blood stream infection (aOR 3.02, 95% CI 1.71, 5.34, p

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.

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.

Background The Human T-cell Lymphotropic Virus Type-1 (HTLV-1) is a blood-borne pathogen and etiological agent of Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HTLV-1 has currently infected up to 10 million globally with highly endemic areas in Japan, Africa, the Caribbean and South America. We have previously shown that Extracellular Vesicles (EVs) enhance HTLV-1 transmission by promoting cell–cell contact. Results Here, we separated EVs into subpopulations using differential ultracentrifugation (DUC) at speeds of 2 k (2000×g), 10 k (10,000×g), and 100 k (100,000×g) from infected cell supernatants. Proteomic analysis revealed that EVs contain the highest viral/host protein abundance in the 2 k subpopulation (2 k > 10 k > 100 k). The 2 k and 10 k populations contained viral proteins (i.e., p19 and Tax), and autophagy proteins (i.e., LC3 and p62) suggesting presence of autophagosomes as well as core histones. Interestingly, the use of 2 k EVs in an angiogenesis assay (mesenchymal stem cells + endothelial cells) caused deterioration of vascular-like-tubules. Cells commonly associated with the neurovascular unit (i.e., astrocytes, neurons, and macrophages) in the blood–brain barrier (BBB) showed that HTLV-1 EVs may induce expression of cytokines involved in migration (i.e., IL-8; 100 k > 2 k > 10 k) from astrocytes and monocyte-derived macrophages (i.e., IL-8; 2 k > 10 k). Finally, we found that EVs were able to promote cell–cell contact and viral transmission in monocytic cell-derived dendritic cell. The EVs from both 2 k and 10 k increased HTLV-1 spread in a humanized mouse model, as evidenced by an increase in proviral DNA and RNA in the Blood, Lymph Node, and Spleen. Conclusions Altogether, these data suggest that various EV subpopulations induce cytokine expression, tissue damage, and viral spread.

Adult T-cell leukemia/lymphoma (ATLL) is caused by human T-cell leukemia virus type 1 (HTLV-1). HTLV-1-associated mRNA, including HBZ and tax, is deeply involved in the pathogenesis of ATLL. Using 88 ATLL tissue samples, we performed in situ mRNA analysis of HBZ and tax, and investigated its association with clinicopathological characteristics of ATLL. The median value of HBZ signals (/1000 ATLL cells) was 795.2 (range: 0.4–4013.1) and of tax signals (/1000 ATLL cells) was 5.1 (range: 0.1–891.2). The low-expression HBZ group displayed significant increase in the number of skin lesion (P = 0.0283). The high-expression tax group displayed significant increase in the number of PD-1-positive tumor-infiltrating lymphocytes (P

Genetic alterations in adult T‐cell leukemia/lymphoma (ATLL), a T‐cell malignancy associated with HTLV‐1, and their clinical impacts, especially from the perspective of viral strains, are not fully elucidated. We employed targeted next‐generation sequencing and single nucleotide polymorphism array for 89 patients with ATLL in Okinawa, the southernmost islands in Japan, where the frequency of HTLV‐1 tax subgroup‐A (HTLV‐1‐taxA) is notably higher than that in mainland Japan, where most ATLL cases have HTLV‐1‐taxB, and compared the results with previously reported genomic landscapes of ATLL in mainland Japan and the USA. Okinawan patients exhibited similar mutation profiles to mainland Japanese patients, with frequent alterations in TCR/NF‐ĸB (eg, PRKCB, PLCG1, and CARD11) and T‐cell trafficking pathways (CCR4 and CCR7), in contrast with North American patients who exhibited a predominance of epigenome‐associated gene mutations. Some mutations, especially GATA3 and RHOA, were detected more frequently in Okinawan patients than in mainland Japanese patients. Compared to HTLV‐1‐taxB, HTLV‐1‐taxA was significantly dominant in Okinawan patients with these mutations (GATA3, 34.1% vs 14.6%, P = .044; RHOA, 24.4% vs 6.3%, P = .032), suggesting the contribution of viral strains to these mutation frequencies. From a clinical viewpoint, we identified a significant negative impact of biallelic inactivation of PRDM1 (P = .027) in addition to the previously reported PRKCB mutations, indicating the importance of integrated genetic analysis. This study suggests that heterogeneous genetic abnormalities in ATLL depend on the viral strain as well as on the ethnic background. This warrants the need to develop therapeutic interventions considering regional characteristics., Targeted next‐generation sequencing and single nucleotide polymorphism array were applied to analyze aggressive adult T‐cell leukemia/lymphoma in Okinawa, which were not included in prior genomic studies. Our results showed that HTLV‐1 tax subgroup‐A was associated with high alteration frequencies in GATA3 and RHOA. Clinically, biallelic alterations, not heterozygous deletions or mutations, of PRDM1 were significantly associated with poor prognosis.

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.

Hypoxia regulates fibroblast function by changing intracellular signaling and secretion factors, that influence the states of nearby cells. In this work, we investigated how medium (CM) from human adult dermal fibroblasts (HDFs) cultured in normoxic and hypoxic conditions affected cervical cancer (HeLa) cells. The HeLa cells showed decreased cell viability, increased apoptosis, and cell cycle arrest in response to CM from hypoxic-cultured HDFs (H-CM) compared with CM from normoxic-cultured HDFs (N-CM). Among the proteins up-regulated (>2-fold) in H-CM compared with N-CM, lymphotoxin-beta receptor (LTBR) decreased the viability of HeLa cells. Among the intracellular proteins down-regulated (>2-fold) in HeLa cells treated with H-CM compared with N-CM, the most enriched biological process GO term and KEGG pathway were protein deubiquitination and hsa05166:HTLV-I infection, respectively. In the protein–protein interaction network of intracellular proteins with altered expression (>2-fold), 1 up-regulated (TNF) and 8 down-regulated (ESR1, MCL1, TBP, CD19, LCK, PCNA, CHEK1, and POLA1) hub proteins were defined. Among the down-regulated hub proteins, the most enriched biological process GO term and KEGG pathway were leading strand elongation and hsa05166:HTLV-I infection, respectively. This study reveals that H-CM had stronger anti-cancer effects on cervical cancer cells than N-CM and induced intracellular signaling patterns related to those enhanced anti-cancer effects.

Human T-lymphotropic viruses 1 and 2 (HTLV-1 and HTLV-2) are retroviruses that originated on the African continent and dispersed throughout other continents through human migratory flows. This study describes the prevalence of HTLV-1 and HTLV-2 infection in residents of 11 quilombo remnant communities in the state of Pará, Brazil, and the associated risk factors. A total of 859 individuals (334 men and 525 women), aged between 7 and 91 years, participated in the study. All subjects answered a questionnaire with questions on sociodemographic characteristics and on risk factors associated with HTLV infection, and blood samples were collected and separated into plasma and leukocytes. An immunoenzymatic assay (ELISA; Murex HTLV-I+II, DiaSorin, Dartford, UK) was used as a screening test, and positive samples were subjected to line immunoassay confirmatory tests (Inno-LIA HTLV I/II Score FUJIREBIO) and DNA extraction for subsequent real-time PCR to differentiate the viral type. Four of the 859 individuals were seropositive for HTLV. HTLV-1 infection was confirmed in one individual from the Itamoari community (0.92%), and HTLV-2 infection was confirmed in two individuals from São Benedito (3.17%) and in one individual from Arimandeua (2.22%). Blood transfusion was the only risk factor associated with HTLV infection in this study. This study reports the occurrence of HTLV-1 and HTLV-2 in quilombo remnant communities in the state of Pará. Considering the African origin of the virus and its introduction into Brazil from the slave trade, the continued evaluation of quilombola communities in the state of Pará is essential to better characterize the distribution of infections in these populations and to create public health policies for the control of the spread of the virus and associated diseases.

IntroductionTo identify the prevalence of infection in the urban area of the capital city of Belém, Brazil, the Laboratory of Virology of the Federal University of Pará implemented, as a public service, serological screening for human T-lymphotropic viruses 1 and 2 (HTLV-1/2) infection and, if necessary, counseling service and referral to specialized medical care. The project is funded by the National Council of Science and Technology, the Ministry of Health of Brazil and the Pan American Health Organization.MethodsFrom January 2020 to June 2021, 1,572 individuals of both sexes were approached to answer a questionnaire and were tested using an enzyme immunoassay (Murex HTLV-I+II, DiaSorin, Dartford, UK). Seropositive samples were confirmed as HTLV-1 and HTLV-2 infection by line immunoassay (INNO-LIA® HTLV I/II Score, Fujirebio, Japan) and/or by real-time polymerase chain reaction. G and Fisher's exact tests were applied to identify the association between epidemiological characteristics and HTLV-1/2 infection.ResultsOf the 1,572 screened individuals, 63.74% were females between the ages of 30 and 59 years (49.04%). Infection was confirmed in six individuals (0.38%), among whom three (0.19%) were infected with HTLV-1 and three with HTLV-2 (0.19%). Blood transfusion before 1993 was the main risk factor associated with the route of exposure to the virus (p = 0.0442). The infected individuals were referred to a counseling session with a nursing professional, and two patients who manifested signs and symptoms suggestive of myelopathy associated with HTLV were referred to a neurologist.ConclusionThe implementation of the screening service revealed the occurrence of moderate endemicity of HTLV-1/2 in Belém, reinforcing the importance of continuing the service as a means of establishing an early diagnosis and providing counseling as a measure to prevent and control viral transmission in the general population.

AimTo perform a systematic review to describe the available findings on clinical outcomes in HIV-1 and HTLV-1/HTLV-2 co-infected individuals since 1995.DesignThis Systematic Review used PECO criteria follow by PRISMA reporting guidelines and registered as CRD42021279062 (Prospero database). The Newcastle-Ottawa Scale assessed the methodological quality of included studies.Data Collection and AnalysisA systematical search in PubMed/MEDLINE, Embase, Web of Sciences databases for cross-sectional, case-control, or cohort studies design to identify clinical and laboratorial outcomes related to HIV-1 and HTLV-1/2 coinfection. Search strategy: [(“HIV-1” AND “HTLV-1” OR “HTLV-2”) AND (“Coinfection”) AND (1990/01/01:2021/12/31[Date- Publication])].ResultsA total of 15 articles were included on this systematic review describing data of 2,566 mono and coinfected patients, 58% male, with mean age was 35.7 ± 5.7 years. HIV-1 and HTLV-1 coinfected patients were more likely to had shorter survival and faster progression to death or mortality than monoinfected ones. Coinfected had higher CD4 cell counts and less likelihood of ART use. In addition, higher frequency of diseases like ichthyosis (22.2 vs. 6.8%), scabies (18.6 vs. 0%), candidiasis (42 vs. 12%), Strongyloidiasis (15.4 vs. 2%) and neurological manifestations like encephalopathy, peripheral neuropathy and HAM/TSP were more frequently reported in coinfected patients.ConclusionsHIV-1 and HTLV-1 coinfection and HIV-1 and HTLV-1 /2 triple coinfection were related to shorter survival, higher mortality rate, and faster progression to death, while coinfection by HIV-1/HTLV-2 seems to have neutral association with longer survival, slower AIDS progression, and lower mortality rate. The available evidence indicates an urgent need for prevention and control measures, including screening, diagnosis, and treatment of HIV-1 and HTLV-1/2 coinfected patients. Test-and-treat strategy for patients living with HIV in areas endemic for HTLV infection is mandatory, to avoid the risks of delayed therapy and death for coinfected patients.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42021279062.

Background The forkhead box protein 3 (FOXP3) transcription factor is one of the main markers of immunological suppression in different pathological profiles, and the presence of polymorphic variants may alter the gene expression of this factor. Despite descriptions of an association between the presence of the rs2232365 polymorphism and chronic diseases, the role of the sex variant in this context has not yet been elucidated, as the FOXP3 gene is located on the human sex chromosome X. Results To contribute to this topic, 323 women and 373 men were enrolled in the study, of which 101 were diagnosed with chronic viral liver diseases (39 women and 62 men), 67 with HTLV-1 infection (44 women and 23 men), 230 with coronary artery disease (91 women and 139 men) and 298 healthy and uninfected blood donors (149 women and men). They were genotyped for the rs2232365 polymorphism. The rs2232365 polymorphism was associated with clinical and pathological aspects and biomarkers of viral infections only in men, with functional differences between different infections. Conclusions A relationship is suggested between sex and FOXP3 rs2232365 polymorphism, resulting in different biological repercussions.

Adult T-cell leukemia (ATL) is a life-threatening malignant neoplasm of CD4+ T cells resulted from human T-cell leukemia virus type I (HTLV-I). Tax1 protein of HTLV-I can induce malignant proliferation of T-cells through modulating the expression of growth factors such as platelet-derived growth factor (PDGF). Here, we aimed to investigate the proviral load (PVL) of HTLV-I in ATL, and also to evaluate mRNA expression of B chain of PDGF and PDGF-β receptor in ATL patients and HTLV-I-infected healthy carriers. To this end, peripheral blood mononuclear cells (PBMCs) were isolated by using Ficoll-Histophaque density centrifugation. The mean of HTLV-I PVL in ATL patients (42759 ± 15737 copies/104 cells [95% CI, 9557-75962] was significantly (p = 0.01) higher than that in healthy carries (650 ± 107 copies/104 cells [95% CI, 422-879], respectively. The HTLV-I PVL in ATL patients exhibited a significant correlation with PBMC count (R= 0.495, p= 0.001). The mRNA expression of Tax, B chain of PDGF, and PDGF-β receptor genes was significantly higher in healthy patients than patients with ATL. In conclusion, the expression of the canonical PDGFβ and its receptor, and their correlation with Tax expression cannot be a suitable indicator and/or prognostic factor for progression of ATL in HTLV-I carriers. This article is protected by copyright. All rights reserved.

It is estimated that about 10-20 million peoples are infected with human T-cell leukemia virus type 1 (HTLV-1) around the world and suffered from HTLV-related diseases. The present study was aimed to evaluate the cellular immunity, T-cell activation, humoral immunity, and inflammatory response hallmarks which affect HTLV-1-associated disease progression. A total of 78 participants were included in the study, comprising 39 HTLV-1 asymptomatic careers (ACs) and 39 healthy controls. The HTLV-proviral load (PVL) was determined via real-time PCR technique, and anti-HTLV antibody, sIL2R, sCD30, Neoptrin, hs-CRP, IgE, anti-VCA, anti-EBNA, and anti-EA were assessed by ELISA method. Mean PVL in ACs was 352.7 ± 418.7 copies/104 PBMCs. A significant higher level of sIL-2R was observed in ACs (P < 0.0001). Anti-VCA antibody titer in ACs and healthy controls was 80.72 ± 105.95 and 156.05 ± 130.71, respectively (P = 0.007). Intriguingly, suppression in ACs immune response was not observed. Resultantly, HTLV-1 infection has no effect on the humoral immune response in ACs but greater T-cell activation and function cellular responses were detected. Finally, more studies on various immune markers in adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients are greatly needed to illuminate the association of ACs' immune status with the development of the related diseases.

Background: Blood-borne viruses (BBVs) are one of the most important public health concerns. South Khorasan has a long border with Afghanistan and concern has risen there about blood-borne oncogenic viral infections. The aim of the present study was to evaluate the prevalence and associated risk factors of human T-lymphotropic virus 1 (HTLV-1) and co-infections of BBVs in Birjand, Iran’s eastern border. Methods: In this cross-sectional study, 3441 subjects were tested for sero-prevalence of HTLV-1 by ELISA. The data on demographic features, HTLV-1-related risk factors and other characteristics of the population were analyzed by Pearson chi-square and logistic regression tests. Finally, the co-infection of BBVs was evaluated in the study. Results: The prevalence of HTLV-1 was 0.3% (95% CI: 0.12–0.48). Notably, the sero-prevalence of HIV, hepatitis B virus (HBV), hepatitis D virus (HDV), and hepatitis C virus (HCV) in our previous studies was reported at 0%, 0.2%, 1.2% and 1.6%, respectively. The results indicated that the occurrence of HTLV-1 infection was associated only with the history of hospitalization (odds ratio [OR]: 0.27, 95% CI: 0.07–0.97, with P = 0.04). The co-infection of HBV with HCV was the most common (2.35%), while a co-infection rate of 1.17% was found for both HBV/HTLV-1 and HBV/HDV. Conclusion: Although a higher prevalence of the viruses was expected, it was close to the overall Iranian population. With respect to close relationship with an HTLV-1 endemic area (Mashhad and Neyshabour), the prevalence is very low; however, more attention is needed. Our findings reinforce the importance of increasing knowledge about BBV-related health risk behaviors to prevent the emergence of new cases, especially in low-risk populations.

Adult T-cell leukemia-lymphoma (ATL) is an aggressive hematological malignancy of CD4+ T cells transformed by human T-cell lymphotropic virus-1 (HTLV-1). Most HTLV-1–infected individuals are asymptomatic, and only 3% to 5% of carriers develop ATL. Here, we describe the contribution of aberrant DNA methylation to ATL leukemogenesis. HTLV-1–infected T-cells and their uninfected counterparts were separately isolated based on CADM1 and CD7 expression status, and differentially methylated positions (DMPs) specific to HTLV–infected T cells were identified through genome-wide DNA methylation profiling. Accumulation of DNA methylation at hypermethylated DMPs correlated strongly with ATL development and progression. In addition, we identified 22 genes downregulated because of promoter hypermethylation in HTLV-1–infected T cells, including THEMIS, LAIR1, and RNF130, which negatively regulate T-cell receptor (TCR) signaling. Phosphorylation of ZAP-70, a transducer of TCR signaling, was dysregulated in HTLV-1–infected cell lines but was normalized by reexpression of THEMIS. Therefore, we hypothesized that DNA hypermethylation contributes to growth advantages in HTLV-1–infected cells during ATL leukemogenesis. To test this idea, we investigated the anti-ATL activities of OR-1200 and OR-2100 (OR21), novel decitabine (DAC) prodrugs with enhanced oral bioavailability. Both DAC and OR21 inhibited cell growth, accompanied by global DNA hypomethylation, in xenograft tumors established by implantation of HTLV-1–infected cells. OR21 was less hematotoxic than DAC, whereas tumor growth inhibition was almost identical between the 2 compounds, making it suitable for long-term treatment of ATL patient-derived xenograft mice. Our results demonstrate that regional DNA hypermethylation is functionally important for ATL leukemogenesis and an effective therapeutic target.

A high proviral load (PVL) is recognized as a risk factor for human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), but there is a lack of prospective studies evaluating whether or not HTLV-1 carriers with high PVL are at risk of developing HAM/TSP or other HTLV-1-related diseases. Here, we compare the incidence of clinical manifestations and the cytokine levels in 30 HTLV-1 carriers with high (> 50,000 copies/106 PBMC) and an equal number of subjects with low proviral load. Participants were followed for 3 to 16 years (median of 11 years). The PVL, IFN-γ, TNF, and IL-10 levels were quantified at entry and at the end of the follow-up. Among the self-reported symptoms in the initial evaluation, only the presence of paresthesia on the hands was more frequent in the group with high PVL (p p

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is chronic myelopathy characterized by slowly progressive spastic paraparesis and urinary dysfunction. A few biomarkers in the cerebrospinal fluid are known to be related to disease activity, but no biomarker has been reported in peripheral blood. This study aims to explore the expression level of the adhesion molecule during the expression level of the adhesion molecule among HAM/TSP disease activity. In lymphocyte function-associated antigen 1 and DNAX accessory molecule 1, no variation in expression levels specific to HTLV-1 infection was observed in CD4-positive T cells; however, TSLC1 expression was higher in HAM patients than in asymptomatic carriers and non-infected persons. TSLC1 tended to be higher in patients whose symptoms were worsening. On the contrary, the expression level of TSLC1 in CD8-positive T cells was lower in HAM patients than in asymptomatic carriers, and this tendency was stronger in patients whose symptoms had deteriorated. No significant correlation was found between TSLC1 and either of the transcription factors Tax or HBZ in any T cell group. Therefore, TSLC1 expression in CD4-positive T cells might be a useful biomarker of HAM/TSP disease activity.

Aims Dermatopathic reaction is a histopathological finding of lymph nodes that usually occurs in patients with inflammatory pruritic cutaneous lesions. However, it is sometimes seen in patients with cutaneous T cell lymphoma. Adult T cell leukaemia/lymphoma (ATLL) is a T cell malignancy caused by infection with human T cell leukaemia virus type I (HTLV-1), which is frequently accompanied by cutaneous lesions. However, the detailed clinicopathological characteristics of the dermatopathic reaction of lymph nodes in ATLL patients and HTLV-1 carriers, addressed in this study, remains to be clarified. Methods and results We retrospectively analysed 18 nodal lesions with dermatopathic reaction in HTLV-1 carriers. Axillary and inguinal lymph nodes were the primary affected tissues. Three cases with atypical lymphoid cell infiltration were defined as ATLL with dermatopathic reaction (ATLL-D), showing an abnormal T cell immunophenotype and T cell monoclonality. Two of the three ATLL-D patients died 14 and 7 months after diagnosis (the third case had a very short follow-up). The other 15 patients were indistinguishable from reactive lesions and were defined as HTLV-1-associated lymphadenitis with dermatopathic reaction (HAL-D). They showed an indolent clinical course, with only one case eventually transforming to aggressive disease. Conclusions Lymph node lesions accompanied by dermatopathic reaction in HTLV1 carriers represent a spectrum that includes reactive and neoplastic conditions. HAL-D should be distinguished from ATLL-D, especially to avoid overtreatment.

IntroductionJapan is the most endemic of the developed nations in terms of human T-lymphotropic virus type 1 (HTLV-1) infection. Japan has been tackling HTLV-1 infection and has made remarkable progress. In ophthalmology, awareness of the association between HTLV-1 infection and uveitis has been increasing since the 1990s, when the relationship was first established. Here, we describe a nationwide survey and analysis of the current state of medical care for HTLV-1-associated uveitis (HAU) at ophthalmic facilities in Japan.MethodsA questionnaire survey covered all university hospitals in Japan that were members of the Japanese Ophthalmological Society and all regional core facilities that were members of the Japanese Ocular Inflammation Society. Survey data were collected, and nationwide data on the state of medical care for HAU were tallied and analysed.ResultsOf the 115 facilities, 69 (60.0%) responded. HAU was most commonly diagnosed ‘based on blood tests and characteristic ophthalmic findings’. Overall, 86.8% of facilities perform testing for HTLV-1 antibodies during medical care for diagnosing uveitis, with 58.3% routinely performing testing. Facilities with experience in providing medical care for HAU accounted for 67.6%. The survey also revealed that 85.5% of facilities had seen no decrease in the number of patients with HAU.ConclusionsIn the two decades since the establishment of HAU as a pathological entity, the majority of facilities in Japan have started performing testing for HTLV-1 antibodies when considering differential diagnoses for uveitis. Our data suggest that providing information on HTLV-1 infection to ophthalmologists in Japan has been successfully implemented.

Introduction and objectives Hepatitis C virus (HCV) and human T-cell lymphotropic virus type 1 (HTLV-1) infections have chronic courses. HCV is primarily transmitted via the hematogenous route, whereas HTLV-1 is primarily transmitted sexually, although it can also be transmitted by blood. Individuals chronically infected with either HTLV-1 or HCV can differ in terms of behavioral characteristics and personality traits. This study compared the occurrence of risk behaviors and impulsivity aspects between HCV and HTLV-1 carriers. Materials and methods Observational, comparative and cross-sectional study that involved a sample of outpatients who had HCV or HLTV-1, by way of a sociodemographic and behavioral questionnaire and the Barratt Impulsiveness Scale – BIS-11. 143 individuals with HCV and 113 individuals with HTLV-1 were evaluated. Results There was a difference with regards to gender among patients, with mostly males affected in the HCV group. Risk behaviors commonly mediated by impulsiveness were significantly more frequent in the HCV group. Similarly, overall impulsiveness and domain nonplanning were higher in the HCV group. Multivariate analysis showed that increased age, male gender, higher nonplanning scores and HCV infection were independent factors for the occurrence of risk behaviors. Both groups presented high rates of other sexually transmitted diseases and a low rate of condom use in sexual relations. Conclusions This study confirms the higher rate of risk behaviors and the levels of impulsiveness commonly observed in patients with HCV, along with comparisons to patients with HTLV-1.