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BackgroundHTLV-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 methodsWe 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.ResultsWe found that systemic IL-6 was positively correlated with both age (r = 0.50, p

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 marker KLRB1 (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.

The Democratic Republic of the Congo (DRC) has a history of nonhuman primate (NHP) consumption and exposure to simian retroviruses yet little is known about the extent of zoonotic simian retroviral infections in DRC. We examined the prevalence of human T-lymphotropic viruses (HTLV), a retrovirus group of simian origin, in a large population of persons with frequent NHP exposures and a history of simian foamy virus infection. We screened plasma from 3,051 persons living in rural villages in central DRC using HTLV EIA and western blot (WB). PCR amplification of HTLV tax and LTR sequences from buffy coat DNA was used to confirm infection and to measure proviral loads (pVLs). We used phylogenetic analyses of LTR sequences to infer evolutionary histories and potential transmission clusters. Questionnaire data was analyzed in conjunction with serological and molecular data. A relatively high proportion of the study population (5.4%, n = 165) were WB seropositive: 128 HTLV-1-like, 3 HTLV-2-like, and 34 HTLV-positive but untypeable profiles. 85 persons had HTLV indeterminate WB profiles. HTLV seroreactivity was higher in females, wives, heads of households, and increased with age. HTLV-1 LTR sequences from 109 persons clustered strongly with HTLV-1 and STLV-1 subtype B from humans and simians from DRC, with most sequences more closely related to STLV-1 from Allenopithecus nigroviridis (Allen's swamp monkey). While 18 potential transmission clusters were identified, most were in different households, villages, and health zones. Three HTLV-1-infected persons were co-infected with simian foamy virus. The mean and median percentage of HTLV-1 pVLs were 5.72% and 1.53%, respectively, but were not associated with age, NHP exposure, village, or gender. We document high HTLV prevalence in DRC likely originating from STLV-1. We demonstrate regional spread of HTLV-1 in DRC with pVLs reported to be associated with HTLV disease, supporting local and national public health measures to prevent spread and morbidity.

BackgroundHuman T-Cell Lymphotropic Viruses (HTLV) type 1 and type 2 account for an estimated 5 to 10 million infections worldwide and are transmitted through breast feeding, sexual contacts and contaminated cellular blood components. HTLV-associated syndromes are considered as neglected diseases for which there are no vaccines or therapies available, making it particularly important to ensure the best possible diagnosis to enable proper counselling of infected persons and avoid secondary transmission. Although high quality antibody screening assays are available, currently available confirmatory tests are costly and have variable performance, with high rates of indeterminate and non-typable results reported in many regions of the world. The objective of this project was to develop and validate a new high-performance multiplex immunoassay for confirmation and discrimination of HTLV-1 and HTLV-2 strains.Methodology/principal findingsThe multiplex platform was used first as a tool to identify suitable antigens and in a second step for assay development. With data generated on over 400 HTLV-positive blood donors sourced from USA and French blood banks, we developed and validated a high-precision interpretation algorithm. The Multi-HTLV assay demonstrated very high performance for confirmation and strain discrimination with 100% sensitivity, 98.1% specificity and 100% of typing accuracy in validation samples. The assay can be interpreted either visually or automatically with a colorimetric image reader and custom algorithm, providing highly reliable results.Conclusions/significanceThe newly developed Multi-HTLV is very competitive with currently used confirmatory assays and reduces considerably the number of indeterminate results. The multiparametric nature of the assay opens new avenues to study specific serological signatures of each patient, follow the evolution of infection, and explore utility for HTLV disease prognosis. Improving HTLV diagnostic testing will be critical to reduce transmission and to improve monitoring of seropositive patients.

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in 1-5% of HTLV-1-infected individuals. Previous studies by us and others have shown that the expression of negative immune checkpoint receptors (NCRs) is significantly increased on CD8 T cells in various chronic viral infections and are associated with poor anti-viral immunity. We have previously identified the differential expression of NCRs on CD8 T cells in blood from patients with HAM/TSP and in central nervous system (CNS) tissues of HTLV-1 infected humanized mice and defined the association with neurological complications. In this study, we determined the co-expression patterns of several key NCRs (PD-1, TIGIT, TIM-3, and LAG-3) and their cognate ligands in HTLV-1 infection and assessed how combination strategies targeting these pathways would impact HTLV-1-specific CD8 T-cell effector functions as an approach to reduce CNS disease outcomes. We found that global CD8 T cells from HAM/TSP patients co-express multiple NCRs at significantly higher frequencies than asymptomatic carriers (AC). Moreover, NCR ligands (PVR and PD-LI) on both plasmacytoid and myeloid dendritic cells were also expressed at higher frequencies in HAM/TSP compared to AC. In both AC and HAM/TSP subjects, combination dual PD-L1/TIGIT or triple PD-L1/TIGIT/TIM-3 blockade with monoclonal antibodies resulted in increases in intracellular cytokine expression in CD8 T cells after virus stimulation, particularly CD107a, a marker of degranulation, and TNF-α, a key cytokine that can directly inhibit viral replication. Interestingly, almost all blockade combinations resulted in reduced IL-2+ HTLV-1-specific CD8 T cell frequencies in HAM/TSP subjects, but not in AC. These results define a novel combinatorial NCR immunotherapeutic blockade strategy to reduce HAM/TSP disease burden.

BACKGROUND AND OBJECTIVES: Currently, HTLV screening is not performed in South Africa (SA). This report describes an economic assessment (budget impact and cost-effectiveness) of implementing different HTLV screening strategies. METHODS: A modified version of the Alliance of Blood Operators risk-based decision-making framework was used to assess the risk and consequences of HTLV in the blood supply in SA. We developed a deterministic model of the cost and consequences of four screening strategies: none, universal, all donors once and first time donors only assuming a transfusion-transmission (TT) efficiency of 10% and a manifestation of clinical disease of 6%. RESULTS: Unscreened blood results in 3·55 symptomatic TT-HTLV cases and a total healthcare cost of Rand (R)3 446 950 (US Dollars (USD)229 800) annually. Universal screening would cost R24 000 000 (USD1 600 000) per annum and prevent 3·54 (99·8%) symptomatic TT-HTLV cases in the first year and 0·55 (98·4%) symptomatic TT-HTLV cases in the second year at a cost per TT-HTLV prevented of R6 780 000 (USD450 000) in year one and R43 254 000 (USD2 890 000) in year two. Screening all donors once would cost R16,200,000 (USD1 080 000) or R4 600 000 (USD306 000) per symptomatic TT-HTLV infection prevented in year one. Total costs decrease to R5 100 000 (USD340 000) in year 2 but the cost per TT-HTLV prevented increases to R10 700 000 (USD713 333). CONCLUSION: This analysis contributed to the decision not to implement HTLV screening as the healthcare budget and particularly the budget for blood transfusion in SA is insufficient to provide appropriate treatment. Arguably, available resources can be more efficiently utilized in other healthcare programs.

Background and objectivesDonated blood is not currently screened for human T-cell lymphotropic virus (HTLV) in South Africa. Several small studies have detected HTLV-1 in South Africa, but prevalence by geographic region or population group is unavailable.Materials and methodsWe performed a large seroprevalence study of South African blood donors during 3 months in 2013. All geographic regions except the Western Cape were included, and Black and Coloured (local term for mixed race) donors were oversampled. Identity-unlinked plasma samples were screened with the Abbott Prism HTLV-1/2 assay, and repeatedly reactive samples were tested by the Inno-LIA HTLV-1/2 Score confirmatory assay. Odds ratios were calculated with multivariable logistic regression.ResultsOf 46 752 donors tested, 133 (0·28%) were initially reactive, 111 (0·24%) repeatedly reactive and 57 (0·12%) confirmed positive for HTLV-1; none were HTLV-2 positive. Prevalence was 0·062% weighted to annual blood donations but highly concentrated in the Black population group (OR = 20·24 CI: 2·77-147·88); higher in females than males (OR = 1·81 CI: 1·06-3·08); and in donors aged >50 years compared to ages 16-19 (OR = 6·4 CI: 2·95-13·86). After controlling for age, sex and population group, there was no difference in prevalence between new and repeat blood donors or among geographic regions within South Africa.ConclusionsWe conclude that HTLV-1 infection is widespread among the Black population of South Africa and its epidemiology is similar to other endemic areas. Because South Africa is increasing its recruitment of Black blood donors, the implications for blood screening require further consideration.

Human T-cell leukemia virus type 1 (HTLV-1) has infected as many as 10 million people worldwide. While 90% are asymptomatic, 5% develop severe diseases including adult T-cell leukemia/lymphoka (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). No vaccine against HTLV-1 exists, and screening programs are not universal. However, patients with chronic HTLV-1 infection have high frequencies of HTLV-1-activated CD8+ T cells, and the two main HLA alleles (A2, A24) are present in 88% of infected individuals. We thus utilized an immunoproteomics approach to characterize MHC-I restricted epitopes presented by HLA-A2+, A24+ MT-2 and SLB-1 cell lines. Unlike traditional motif prediction algorithms, this approach identifies epitopes associated with cytotoxic T-cell responses in their naturally processed forms, minimizing differences in antigen processing and protein expression levels. Out of nine identified peptides, we confirmed six novel MHC-I restricted epitopes that were capable of binding HLA-A2 and HLA-A24 alleles and used in vitro and in vivo methods to generate CD8+ T cells specific for each of these peptides. MagPix MILLIPLEX data showed that in vitro generated epitope-specific CD8+ T cells secreted IFN-ɣ, granzyme B, MIP-1α, TNF-α, perforin and IL-10 when cultured in the presence of MT-2 cell line. Degranulation assay confirmed cytotoxic response through surface expression of CD107 on CD8+ T cells when cultured with MT-2 cells. A CD8+ T-cell killing assay indicated significant antiviral activity of CD8+ T cells specific against all identified peptides. In vivo generated CD8+ T cells similarly demonstrated immunogenicity on ELISpot, CD107 degranulation assay, and MagPix MILLIPLEX analysis. These epitopes are thus candidates for a therapeutic peptide-based vaccine against HTLV-1, and our results provide preclinical data for the advancement of such a vaccine.

Adult T-cell leukemia/lymphoma (ATLL) is a fatal disease caused by human T-cell leukemia virus type 1 (HTLV-1). We retrospectively analyzed 195 patients with ATLL (lymphomatous n = 96, acute n = 80, unfavorable chronic n = 7, chronic n = 5, smoldering n = 3, and unclassified n = 4) diagnosed between 1987 and 2016 (median age 52 years, 77% Afro-Caribbean). Hypercalcemia was associated with acute ATLL (65%, vs 23% lymphomatous) (P = .012). The median survival for patients treated with modern therapies between 2000 and 2016 was 4.1 months for acute, 10.2 months for lymphomatous, 72 months for chronic/smoldering, and not reached for unfavorable chronic type, with 4-year survival rates of 10%, 4%, 60%, and 83%, respectively. The overall response rate (ORR) after first-line multiagent chemotherapy was 78% (complete response [CR] 39%) for acute vs 67% (CR 33%) for lymphomatous ATLL. First-line zidovudine interferon-α (AZT-IFN) resulted in ORR of 56% (CR 23%) for acute (n = 43), 33% (CR 16.5%) for lymphomatous (n = 6), and 86% (CR 29%) for unfavorable chronic ATLL. The median progression-free survival (PFS) in patients with aggressive ATLL who achieved CR after AZT-IFN was 48 months vs 11 months after chemotherapy (P = .003). Allogeneic hematopoietic stem cell transplant (allo-HSCT) resulted in a PFS of 24 and 28 months in 2 patients with lymphomatous ATLL. Our results suggest high-dose AZT-IFN is a reasonable up-front option for patients with aggressive leukemic ATLL followed by chemotherapy switch in nonresponders, whereas chemotherapy should be used in lymphomatous type followed by allo-HSCT when feasible.

BackgroundInfection with Human T cell Leukemia Virus type 1 can be associated with myelopathy/tropical spastic paraparesis (HAM/TSP) and other inflammatory diseases. Lymphocytes from about half of Human T cell Leukemia Virus type 1-infected subjects spontaneously proliferate in vitro, and how this phenomenon relates to symptomatic disease and viral burden is poorly understood.ObjectiveTo evaluate T-cell proliferation in vitro among patients co-infected with Human T cell Leukemia Virus type 1/Hepatitis C Virus/Human Immunodeficiency Virus type 1.Material and methodsFrom 610 Human T cell Leukemia Virus-infected patients of the Human T cell Leukemia Virus outpatient clinic from Institute of Infectious Diseases "Emilio Ribas" in São Paulo, 273 agreed to participate: 72 had HAM/TSP (excluded from this analysis) and 201 were asymptomatic, a classification performed during a regular neurological appointment. We selected the subgroup made up only by the 201 asymptomatic subjects to avoid bias by the clinical status as a confounder effect, who had laboratory results of Human T cell Leukemia Virus type 1 proviral load and T-cell proliferation assay in our database. They were further grouped according to their serological status in four categories: 121 Human T cell Leukemia Virus type 1 asymptomatic mono-infected carriers; 32 Human T cell Leukemia Virus type 1/Hepatitis C Virus, 29 Human T cell Leukemia Virus type 1/Human Immunodeficiency Virus type 1, and 19 Human T cell Leukemia Virus type 1/Human Immunodeficiency Virus type 1/Hepatitis C Virus co-infected patients. Clinical data were obtained from medical records and interviews. DNA Human T cell Leukemia Virus type 1 proviral load (PVL) and T-cell proliferation (LPA) assay were performed for all samples.ResultsFrom a total of 273 subjects with Human T cell Leukemia Virus type 1, 80 presented co-infections: 29 had Human Immunodeficiency Virus type 1, 32 had Hepatitis C Virus, and 19 had Human Immunodeficiency Virus type 1 and Hepatitis C Virus. Comparing the groups based on their serological status, independently of being asymptomatic carriers, we observed a significant increase of PVL (p

Background: Primary gastric lymphomas account for less than 5% of non-Hodgkin lymphomas (NHL). The vast majority of primary gastric lymphomas are high-grade Bcell lymphomas. Primary gastric T-cell lymphomas are very rare and are usually associated with HTLV-1 infection in endemic regions. Material and methods. We describe the case of a middle-aged female patient who presented with pneumoperitoneum due to a perforated gastric ulcer, wasting syndrome, and skin and oral lesions. Results. Histopathology and immunohistochemistry confirmed primary gastric T-cell lymphoma with skin involvement. The serology for HTLV-1, Epstein-Barr virus and HIV were negative. Conclusion. The aim of this report is to present this extremely rare presentation of primary gastric lymphoma. [ABSTRACT FROM AUTHOR]

Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL) in human T-cell lymphotropic virus (HTLV) infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1), 45 human T-cell lymphotropic virus type 2 (HTLV-2), and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST) cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S) ratio (a measure of TL) and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs) using quantitative PCR (qPCR). Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322). TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection.

Many countries currently perform antibody screening for HTLV-1 infection in blood donors, and this intervention is likely cost-effective in preventing HTLV-1 related diseases in high prevalence countries. However, a number of high-income countries with low prevalence of HTLV-1 infection also perform universal HTLV-1 screening and debate has arisen regarding the cost-effectiveness of these strategies. Filter-based leukoreduction is likely to substantially reduce HTLV-1 transmission by removing infected lymphocytes, but actual laboratory data on its efficacy is currently lacking. Similarly, cost-effectiveness research on HTLV-1 prevention strategies is limited by poor data on prevalence, transmission efficacy and the cost of treating HTLV1 diseases.

In individuals with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), spasticity is one of the main symptoms. The neurological signs of the disease are well defined, but details of how spasticity appears in these individuals have not been well explored. To describe spasticity location and severity of HAM/TSP individuals. Cross-sectional study with individuals older than 18 years, diagnosed with HAM/TSP and with lower limb spasticity. Pregnant women, individuals with other associated neurological diseases, and those using antispastic drugs were not included. Spasticity was assessed by the Modified Ashworth Scale (MAS), applied to the abductor, adductor, flexor, and extensor muscles of the hips, flexors, and extensors of the knees, dorsiflexors, plantiflexors, evertors, and inverters of the foot. Thirty participants were included. The plantiflexor muscles (90%), knee extensors (80%), knee flexors (63,3%), and adductors (50%) were most frequently affected by spasticity. Twenty-three (76.7%) individuals had mixed spasticity, 5 (16.7%) with distal spasticity and 2 (6.7%) with proximal spasticity. MAS was similar between the lower limbs in at least 6 of the 10 muscle groups of each individual. Spasticity was mostly mixed in the lower limbs, with more frequently mild severity. The individuals were partially symmetrical between the lower limbs. The most affected muscle groups were the plantiflexors, knee extensors and flexors and the hip adductors, consecutively, being predominantly symmetrical. [ABSTRACT FROM AUTHOR]

The human T-cell leukemia retrovirus type-1 (HTLV-1) p30(II) protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation. We have previously demonstrated that p30(II) interacts with the c-MYC oncoprotein and enhances c-MYC-dependent transcriptional and oncogenic functions. However, the molecular and biochemical events that mediate the cooperation between p30(II) and c-MYC remain to be completely understood. Herein we demonstrate that p30(II) induces lysine-acetylation of the c-MYC oncoprotein. Acetylation-defective c-MYC Lys→Arg substitution mutants are impaired for oncogenic transformation with p30(II) in c-myc(-/-) HO15.19 fibroblasts. Using dual-chromatin-immunoprecipitations (dual-ChIPs), we further demonstrate that p30(II) is present in c-MYC-containing nucleoprotein complexes in HTLV-1-transformed HuT-102 T-lymphocytes. Moreover, p30(II) inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. These findings suggest that c-MYC-acetylation is required for the cooperation between p30(II)/c-MYC which could promote proviral replication and contribute to HTLV-1-induced carcinogenesis.

Human T-lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) both cause lifelong persistent infections, but differ in their clinical outcomes. HTLV-1 infection causes a chronic or acute T-lymphocytic malignancy in up to 5% of infected individuals whereas HTLV-2 has not been unequivocally linked to a T-cell malignancy. Virus-driven clonal proliferation of infected cells both in vitro and in vivo has been demonstrated in HTLV-1 infection. However, T-cell clonality in HTLV-2 infection has not been rigorously characterized. In this study we used a high-throughput approach in conjunction with flow cytometric sorting to identify and quantify HTLV-2-infected T-cell clones in 28 individuals with natural infection. We show that while genome-wide integration site preferences in vivo were similar to those found in HTLV-1 infection, expansion of HTLV-2-infected clones did not demonstrate the same significant association with the genomic environment of the integrated provirus. The proviral load in HTLV-2 is almost confined to CD8+ T-cells and is composed of a small number of often highly expanded clones. The HTLV-2 load correlated significantly with the degree of dispersion of the clone frequency distribution, which was highly stable over ∼8 years. These results suggest that there are significant differences in the selection forces that control the clonal expansion of virus-infected cells in HTLV-1 and HTLV-2 infection. In addition, our data demonstrate that strong virus-driven proliferation per se does not predispose to malignant transformation in oncoretroviral infections.

BackgroundOther studies have reported high rates of depression and anxiety among human T-lymphotropic virus Type I (HTLV-I)-infected subjects and have even suggested that HTLV-I causes psychiatric disease.Study design and methodsWe interviewed HTLV-I, HTLV-II, and demographically similar HTLV-seronegative blood donors with the Mini-International Neuropsychiatric Interview. Prevalences of major depression and generalized anxiety disorder in each group were calculated and compared to published US population data. Adjusted odds ratios (aOR) and 95% confidence intervals (CIs) controlling for educational achievement, alcohol intake, and self-reported health status were calculated with multivariate logistic regression.ResultsMajor depression was diagnosed in five (5.4%) of 93 HTLV-I-positive subjects (aOR, 2.19; 95% CI, 0.63-7.55) and 17 (6.6%) of 256 HTLV-II-positive subjects (aOR, 1.61; 95% CI, 0.66-3.927), compared to 12 (2.1%) of 585 HTLV-seronegative blood donors. The prevalence of major depression among infected subjects was comparable to the 6.7% prevalence in the US general population. Generalized anxiety disorder was diagnosed in five (5.4%) HTLV-I-positive subjects (OR, 2.32; 95% CI, 0.74-7.26) and 12 (4.7%) HTLV-II-positive subjects (OR, 1.65; 95% CI, 0.68-4.01), compared to 15 (2.6%) seronegative subjects and 3.1% in the US general population.ConclusionMajor depression and generalized anxiety disorder were not significantly more prevalent among HTLV-I- and HTLV-II-infected former blood donors after controlling for health status and other confounding variables. HTLV-seronegative blood donors had lower prevalences of these conditions than the US population, probably due to a "healthy blood donor effect."

Persistent viruses are hard to be eradicated, even using effective medications, and can persist for a long time in humans, sometimes regardless of treatment. Hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and human T cell lymphotropic virus infections, the most common in our era, are still a challenge despite the increased knowledge about their biology. Most of them are highly pathogenic, some causing acute disease or, more often, leading to chronic persistent infections, and some of the occult, carrying a high risk of morbidity and mortality. However, if such infections were discovered early, they might be eradicated in the near future with effective medications and/or vaccines. This perspective review points out some specific characteristics of the most important chronic persistent viruses. It seems that in the next few years, these persistent viruses may have control by vaccination, epidemiological strategies, and/or treatment.

Human T-cell lymphotropic virus type 1 (HTLV-1) prevalence in Portugal is low and mainly affects immigrants from endemic areas where human immunodeficiency virus (HIV) infection represents a public health problem. Despite the majority of HTLV-1-infected individuals remains asymptomatic, severe pathologies may develop after prolonged viral persistence, namely an aggressive form of leukemia. An increased mortality rate and faster progression to death is often related to HTLV-1/HIV coinfection. Nevertheless, studies showed that some antiretrovirals used in HIV treatment lead to a positive immune response against HTLV-1. This study aimed to analyze epidemiological and clinical data, and to assess the diversity of HTLV-1 strains circulating in infected residents diagnosed in the Portuguese national reference laboratory between 2010 and 2021. Long terminal repeat and env proviral sequences derived from 20 individuals were used to generate phylogenetic trees along with multiples reference sequences from different geographic origins retrieved from the database. Three samples belong to Portuguese natives and 17 belong to immigrants: 15 from several countries of Africa, 1 from South America, and 1 from Europe; 6 patients (30%, mean age 40.3 years) showed HTLV-1-related diseases, and 6 (30%, mean age 45.2 years) were coinfected with HIV/AIDS. The results show that the Cosmopolitan subtype is circulating in Portugal, with 10 sequences being classified as subgroup A, that include Portuguese and natives from S. Tomé and Príncipe with a mean age of 39.4 years, and 10 sequences that segregated into the Senegal cluster derived from natives born in Guinea-Bissau with a mean age of 43.5 years. A high proportion of HTLV-1-related diseases and HIV/AIDS coinfection was observed. Risk behavior practices and the absence of specific control measures, including diagnostic and treatment, may contribute to a silent dissemination of a broad diversity of HTLV-1 strains and, therefore, the increased rate of progression to debilitating diseases. In this manner, an early diagnostic and a molecular surveillance of HTLV-1 transmission remains necessary in Portugal.

Despite the accuracy of confirmatory tests for the diagnosis of human T cell lymphotropic virus (HTLV), inconclusive or false-negative results still occur when diagnosing human T cell lymphotropic virus type 2 (HTLV-2)-positive patients. The goal of this study was to evaluate the sensitivity and accuracy of a confirmatory immunoassay, the Multi-HTLV assay. A total of 246 plasma samples were tested by real-time polymerase chain reaction (qPCR) and used to calculate the sensitivity and typing accuracy of the Multi-HTLV assay. Of the 246 plasma samples, 127 were positive for human T cell lymphotropic virus type 1 (HTLV-1), 112 were positive for HTLV-2, and 7 were positive for both HTLV-1 and HTLV-2. Thereafter, the nonparametric Mann-Whitney U test was used to calculate the concordance between the qPCR test and Multi-HTLV assay in 12 samples with discrepant and inconclusive qPCR results. The Multi-HTLV assay showed high performance in identifying HTLV-1 and HTLV-2 with sensitivities of 97% [95% confidence interval (CI): 0.92-0.98] and 94% (0.87-0.96), respectively. However, due to typing performance (98% for HTLV-1 and 94% for HTLV-2), it had 95% agreement with positive HTLV-1 qPCR results (95% CI: 90.07-97.81) and 86% (78.04-91.01) of HTLV-2 qPCR results were positive. Moreover, this test was able to recognize 80% of indeterminate samples and all HTLV-2 positive samples that showed false-negative qPCR results. Our findings, derived from a substantial number of HTLV-positive samples, underscore the inherent reliability and feasibility of the Multi-HTLV assay, regardless of the molecular testing facilities. Furthermore, the distinctive multiparametric nature of this assay, combined with its straightforward procedural execution, introduces novel perspectives for analyzing specific serological profiles in each patient, as well as the potential for immunological monitoring of disease progression.

Background and Objectives: Serological HTLV-1/2 screening is mandatory for blood donor candidates in Brazil. Our objective was to analyse HTLV test results in blood donors submitted for screening and confirmatory assays in a Brazilian blood bank., Materials and Methods: Retrospective analysis (2017-2022) results of chemiluminescence immunoassays and confirmatory tests for HTLV-1/2 in reactive donors were performed. During the analysed period, three sets of assays were used: (1) Architect rHTLV-I/II + HTLV Blot 2.4 (Western blot [WB]); (2) Alinity s HTLV I/II Reagent Kit + INNO-line immunoassay (LIA) HTLV I/II Score (LIA); (3) Alinity + WB., Results: The analysed period comprised a total of 1,557,333 donations. The mean percentage of HTLV reactive donors using the Architect assay was 0.14%. With the change to the Alinity assay, that percentage dropped 2.3-fold (0.06%). The reactivity rate in the confirmatory tests (1064 samples) ranged from 13.5% to 30.2%, whereas 58.3%-85.9% of samples were non-reactive. The highest rates of positive (30.2%) and indeterminate (11.5%) results were seen using LIA. Considering all analysed samples, those with signal/cut-off ratio (S/CO) >50 were positive in confirmatory tests (positive predictive value, PPV = 100%), whereas samples with S/CO ≤6 are very unlikely to be truly positive (PPV = 0)., Conclusion: The use of the Alinity assay reduced the frequency of false-positive results. Confirmatory tests are important to identify true HTLV infection in blood donors, because more than 58% of initially reactive individuals are confirmed as seronegative. Categorizing S/CO values is useful for assessing the likelihood of true HTLV-1/2 infection., (© 2024 International Society of Blood Transfusion.)

Background: Whether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown., Methods: To investigate humoral immunity after COVID-19 vaccination in HTLV-1 carriers, a multicenter, prospective observational cohort study was conducted at five institutions in southwestern Japan, an endemic area for HTLV-1. HTLV-1 carriers and HTLV-1-negative controls were enrolled for this study from January to December 2022. During this period, the third dose of the COVID-19 vaccine was actively administered. HTLV-1 carriers were enrolled during outpatient visits, while HTLV-1-negative controls included health care workers and patients treated by participating institutions for diabetes, hypertension, or dyslipidemia. The main outcome was the effect of HTLV-1 infection on the plasma anti-COVID-19 spike IgG (IgG-S) titers after the third dose, assessed by multivariate linear regression with other clinical factors., Results: We analyzed 181 cases (90 HTLV-1 carriers, 91 HTLV-1-negative controls) after receiving the third dose. HTLV-1 carriers were older (median age 67.0 vs. 45.0 years, p < 0.001) and more frequently had diabetes, hypertension, or dyslipidemia than did HTLV-1-negative controls (60.0% vs. 27.5%, p < 0.001). After the third dose, the IgG-S titers decreased over time in both carriers and controls. Multivariate linear regression in the entire cohort showed that time since the third dose, age, and HTLV-1 infection negatively influenced IgG-S titers. After adjusting for confounders such as age, or presence of diabetes, hypertension, or dyslipidemia between carriers and controls using the overlap weighting propensity score method, and performing weighted regression analysis in the entire cohort, both time since the third dose and HTLV-1 infection negatively influenced IgG-S titers., Conclusions: The humoral immunity after the third vaccination dose is impaired in HTLV-1 carriers; thus, customized vaccination schedules may be necessary for them., (© 2024. The Author(s).)

Human T-cell leukaemia virus type 1 (HTLV-1) is a human retrovirus that causes adult T-cell lymphoma and HTLV-associated myelopathy. In this issue, Rosadas et al. use data from a recent WHO report to describe how blood banks test for HTLV-1 and how this testing contributes to public health surveillance for the virus. Commentary on: Rosadas et al. HTLV-1 screening of blood donations: we are systematically missing opportunities. Br J Haematol 2023;202:1220-1223., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

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Human T-lymphotropic virus type 1/2 (HTLV-1/2) infection is endemic in Brazil but representative donor prevalence and incidence data are lacking. All blood donations (2007-2009) from three blood centers in Brazil were studied. Samples reactive on one HTLV screening test (EIA) were retested with a different EIA; dual EIA reactivity correlated strongly with a confirmatory Western blot. Prevalence, incidence, and residual transfusion risk were calculated. Among 281,760 first-time donors, 363 were positive for HTLV on both EIAs (135 per 10(5), 95% CI 122-150). Prevalence differed considerably by region, from 83 to 222 per 10(5). Overall incidence rate was 3.6/10(5) person-years and residual transfusion risk was 5.0/10(6) per blood unit transfused. The logistic regression model showed significant associations with: age [adjusted odds ratio (aOR)=5.23 for age 50+ vs.

BackgroundHuman T-lymphotropic virus (HTLV)-I and HTLV-II cause chronic human retroviral infections, but few studies have examined the impact of either virus on survival among otherwise healthy individuals. The authors analyzed all-cause and cancer mortality in a prospective cohort of 155 HTLV-I, 387 HTLV-II, and 799 seronegative subjects.MethodsVital status was ascertained using death certificates, the US Social Security Death Index or family report, and causes of death were grouped into 9 categories. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models.ResultsAfter a median follow-up of 15.9 years, there were 105 deaths: 22 HTLV-I, 41 HTLV-II, and 42 HTLV-seronegative. Cancer was the predominant cause of death, resulting in 8 HTLV-I, 17 HTLV-II, and 15 HTLV-seronegative deaths. After adjustment for confounding, HTLV-I status was not significantly associated with increased all-cause mortality, though there was a positive trend (HR: 1.6, 95% CI: 0.8 to 3.1). HTLV-II status was strongly associated with increased all-cause (HR: 2.4, 95% CI: 1.4 to 4.4) and cancer mortality (HR: 3.8, 95% CI: 1.6 to 9.2).ConclusionsThe observed associations of HTLV-II with all-cause and cancer mortality could reflect biological effects of HTLV-II infection, residual confounding by socioeconomic status or other factors, or differential access to health care and cancer screening.

In Argentina, current procedures to ensure safety of the blood supply for transfusion include reviewing the records of blood donors with particular attention to the serologic detection of specific blood borne infections. Data of 28,483 blood donations received from January 1, 2003 to December 31, 2008 in a public hospital in Buenos Aires were analyzed. Of the 28,483 blood donations, 7,442 (26.1%) were female donors, 14,582 (51.2%) were younger than 35 years old, and 23,746 (83.4%) were Argentine. Among all, only 285 (1.0%) were voluntary donations. The prevalence of HTLV-1/2 was 0.1% (95% CI 0.063-0.15), being 0.07% for HTLV-1 and 0.03% for HTLV-2. The prevalence of HIV-1 was 0.2% (95% CI 0.110-0.206). No HIV-1/HTLV-1/2 co-infections were detected among volunteer donors. During this study period, data confirm that HTLV-1/2 infection was not endemic in Buenos Aires, and that the prevalence of HTLV-1/2 decreased throughout while HIV-1 was stable. Due to the small number of voluntary donations, we could not conduct comparisons to infection rates in replacement donations. Although there have been several ongoing programs aimed at recruiting voluntary blood donations and changing from mostly replacement donations to an altruistic system of blood donations, Argentina is still far from reaching this objective. Additional efforts are needed in order to increase and assure the quality of blood supply in this country.

Background: Screening of pregnant women carrying human T-lymphotropic virus type 1 (HTLV-1) has a crucial role in reducing the number of HTLV-1 carriers. A national HTLV-1 screening program for pregnant women was started in 2011 in Japan. The purpose of this study is to report on the implementation of this nationwide screening program.Methods: This was a retrospective repeated cross-sectional study. We used datasets from surveys of HTLV-1-antibody-positive pregnant women performed by the Japan Association of Obstetricians and Gynecologists in 2011, 2013, and 2016. Outcomes for evaluation included the number of persons (pregnant women) who conducted the screening test, the number of positive persons (women) identified by these tests, and the proportion of positive persons to the number of persons (women) who conducted the tests.Results: Numbers of target facilities changed yearly: 1857 in 2011, 2544 in 2013, and 2376 in 2016. The mean number of screening-test participants increased per facility, but the median increased or decreased. The mean number of positive individuals identified decreased. Multivariate analysis results revealed the number of screenings was slightly reduced yearly, although areas (Kanto and Kinki) and high volume in facility types increased. Regarding the positive rates, some areas (Hokkaido/Tohoku, Kanto, and Chugoku/Shikoku) exhibited decreases or increases by facility type. The number of western blotting (WB) implementations decreased in 2016, positive rates identified by WB decreased in 2016 in all areas, and the number of facility types increased. The number of PCR participants increased in 2016 in Kanto and Kinki, but a decrease in facility type was observed. Positive rates were decreased in all areas (except the central region) but facility types were increased.Conclusions: The nationwide screening program for HTLV-1 in Japan was almost fully implemented. However, regional variations in screening tests were observed during this implementation. Thus, some incentives are needed to encourage proper implementation across all regions. [ABSTRACT FROM AUTHOR]

The infection mechanism and pathogenicity of Human T-lymphotropic virus 1 (HTLV-1) are ambiguously known for hundreds of years. Our knowledge about this virus is recently emerging. The purpose of the study is to design a vaccine targeting the envelope glycoprotein, GP62, an outer membrane protein of HTLV-1 that has an increased number of epitope binding sites. Data collection, clustering and multiple sequence alignment of HTLV-1 glycoprotein B, variability analysis of envelope Glycoprotein GP62 of HTLV-1, population protection coverage, HLA-epitope binding prediction, and B-cell epitope prediction were performed to predict an effective vaccine. Among all the predicted peptides, ALQTGITLV and VPSSSTPL epitopes interact with three MHC alleles. The summative population protection coverage worldwide by these epitopes as vaccine candidates was found nearly 70%. The docking analysis revealed that ALQTGITLV and VPSSSTPL epitopes interact strongly with the epitope-binding groove of HLA-A*02:03, and HLA-B*35:01, respectively, as this HLA molecule was found common with which every predicted epitope interacts. Molecular dynamics simulations of the docked complexes show they form stable complexes. So, these potential epitopes might pave the way for vaccine development against HTLV-1. [ABSTRACT FROM AUTHOR]

Human T-lymphotropic viruses types I and II (HTLV-I and HTLV-II) cause chronic infections of T lymphocytes that may lead to leukemia and myelopathy. However, their long-term effects on blood counts and hematopoiesis are poorly understood. We followed 151 HTLV-I-seropositive, 387 HTLV-II-seropositive, and 799 HTLV-seronegative former blood donors from 5 U.S. blood centers for a median of 14.0 years. Complete blood counts were performed every 2 years. Multivariable repeated measures analyses were conducted to evaluate the independent effect of HTLV infection and potential confounders on 9 hematologic measurements. Participants with HTLV-II had significant (P < .05) increases in their adjusted lymphocyte counts (+126 cells/mm(3); approximately +7%), hemoglobin (+2 g/L [+0.2 g/dL]) and mean corpuscular volume (MCV; 1.0 fL) compared with seronegative participants. Participants with HTLV-I and HTLV-II had higher adjusted platelet counts (+16 544 and +21 657 cells/mm(3); P < .05) than seronegatives. Among all participants, time led to decreases in platelet count and lymphocyte counts, and to increases in MCV and monocytes. Sex, race, smoking, and alcohol consumption all had significant effects on blood counts. The HTLV-II effect on lymphocytes is novel and may be related to viral transactivation or immune response. HTLV-I and HTLV-II associations with higher platelet counts suggest viral effects on hematopoietic growth factors or cytokines.

BACKGROUND: Human T lymphotropic virus types 1 (HTLV-1) and 2 (HTLV-2) are frequent copathogens among individuals infected with human immunodeficiency virus type 1 (HIV-1). The long-term effects of coinfection are unknown, and little information exists regarding how levels of HTLV-1/2 viral burden are affected by antiretroviral medications. METHODS: Factors associated with HTLV-1/2 viral burden were examined in patients with HIV-HTLV-1/2 coinfection. A total of 72 subjects were evaluated. The variables analyzed included HTLV-1/2 proviral load, HTLV-1/2 tax/rex mRNA expression, HIV load, HTLV-1/2 viral antigen detection in peripheral blood mononuclear cell (PBMC) cultures, T cell subsets, demographic variables (age, race, sex, and reported use of injection drugs), and administration of highly active antiretroviral therapy. RESULTS: An HTLV-1/2 proviral DNA copy number >20,000 copies/10(6) PBMCs was significantly associated with the following variables: (1) a positive HTLV-1 Western blot test result, (2) a positive HTLV-1/2 PBMC culture result, (3) a positive tax/rex mRNA result, (4) an HIV load

BackgroundThe human T lymphotropic virus (HTLV)-I or -II proviral load (VL) may be linked to viral pathogenesis, but prospective data on VL and disease outcomes are lacking.MethodsUsing data from a prospective cohort study of HTLV disease outcomes, we examined baseline VLs with real-time quantitative polymerase chain reaction in 122 HTLV-I- and 319 HTLV-II-infected subjects and serial VLs over the course of 6 visits in a subset of 30 HTLV-I- and 30 HTLV-II-infected subjects. Cox and logistic-regression models were used to test baseline associations, and repeated-measures analysis was used to study variations in VL over time.ResultsOver the course of a median of 10.4 years, HTLV-I VLs decreased slightly (slope, -0.017 log(10) copies/10(6) peripheral blood mononuclear cells [PBMCs]/year; P=.042) and HTLV-II VLs did not change (slope, -0.019 log(10) copies/10(6) PBMCs/year; P=.165). Changes in VL over time were associated positively with alcohol use (P=.07) and negatively with black race (P=.03) for HTLV-I and positively with smoking (P=.08) for HTLV-II. In the larger group, there was no association between baseline VL and disease outcomes. In the smaller group with serial VL data, there was an association between increasing VL and bladder or kidney infections for both HTLV-I (P=.005) and HTLV-II (P=.022).ConclusionsHTLV VLs are stable over time, but alcohol and tobacco intake may affect the progression of VLs. The association between increasing VLs and bladder/kidney infection may be explained by early HTLV-related neuropathologic progression.

ObjectiveThe objective of this study was to ascertain the prevalence and to investigate risk factors for human T lymphotropic virus type I/II (HTLV I/II) infection among subjects who tested for HIV at three counseling centers in Porto Alegre, Brazil.MethodsThe authors conducted a cross-sectional study in which subjects screened for HIV were tested for HTLV. Socioeconomic and demographic data, social and sexual behavior, history of having been breastfed, and past blood transfusion or drug use were gathered with a standardized questionnaire.ResultsAmong 2985 participants, 2.4% had HTLV infection confirmed (1.4% HTLV I). The risk increased with age, but there was no difference among genders. The multivariate model shows that injecting cocaine users were 5.2 (95% confidence interval, 2.5-10.7) times more likely to be HTLV I/II-positive than non-injecting cocaine users and HIV infection persisted as an independent risk factor.ConclusionAmong persons presenting at HIV testing centers in Porto Alegre, Brazil, HTLV I was three times more common than HTLV II; injection drug use was the predominant mode of transmission.