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Background: Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of HTLV associated myelopathy/ Tropical Spastic Paraparesis (HAM/TSP) and Adult T cell leukemia/lymphoma (ATLL), in around 2-5% of the infected individuals. Host genetic background might play a role in disease progression. Several previous studies across many countries report HLA haplotype to be one such factor. Here, we sequenced HLA-A, -B and -C of 66 individuals by Sequence-Based Typing (SBT), and compared the frequency of different alleles among ATLL patients, HAM/TSP patients, asymptomatic carriers and non-infected individuals living in Argentina. Results: The frequency of HLA-A, -B and -C alleles largely matched that of the general population in Argentina. We identified HLA-A*02, HLA-B*35 and HLA-C*07 as associated to protection from ATLL (p = 0.031), susceptibility to HAM/TSP (p < 0.001) and susceptibility to ATLL (p = 0.017), respectively. We also found a strong correlation between high proviral load (PVL) and disease (p = 0.008), but were unable to identify any particular allele associated with high or low PVL. Conclusions: We have found HLA-A*02, HLA-B*35 and HLA-C*07 to be associated to protection from ATLL (HLA-A*02) and susceptibility to HAM/TSP (HLA-B*35) or to ATLL (HLA-C*07), respectively. Whereas HLA-A*02 protection from ATLL has already been extensively described in other regions of the world, this is the first report that links HLA-B*35 and an increased susceptibility to HAM/TSP. As for HLA-C*07 it has previously been associated to susceptibility to HAM/TSP in other countries but in our population it has been linked to ATLL. Fil: Benencio, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Fraile Gonzalez, Sindy A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Ducasa, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Page, Kimberly. University of New Mexico; Estados Unidos. University of California; Estados Unidos Fil: Berini, Carolina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Biglione, Mirna Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Background Human T-cell lymphotropic virus type 1 (HTLV-1) spreads silently in the world’s population and causes several syndromes. Among these, HTLV-1 associated myelopathy, also called tropical spastic paraparesis (HAM/TSP), affects the nervous system. It causes sensorimotor losses, spasticity, muscle weakness, voiding and sexual dysfunction, pain, and balance disorders. There is limited knowledge of the feelings, experiences, and coping mechanisms associated with this neglected disease. The objective of the present qualitative study was to investigate the signs, meanings, and practices of people with HAM/TSP, through narratives obtained from focus groups and individual semi-structured face-to-face interviews. Results Thirty-eight individuals diagnosed with HAM/TSP participated in the study. The following categories and subcategories emerged from the participants: Signs—physical signs, symptoms, and discovery of the disease; Meanings—reaction to diagnosis and knowledge of disease, fears, and expectations; Practices—daily life, leisure, religious, and treatment activities. Conclusions People with HAM/TSP suffer from symptoms that limit their social participation, and they are affected by complex and multidimensional feelings. This awareness can contribute to the implementation of public policies—focused on the real perspective of these patients—that provide more directed, empathic, and harmonious care for these individuals.

Background Human T-lymphotropic virus Type 1 (HTLV-1) is a retrovirus that is endemic in some regions of the world. It is known to cause several diseases like adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Serology and molecular methods have been used to detect this virus. Of these, enzyme-linked immunosorbent assay (ELISA) is used as a primary screening method and this is usually followed by western blotting (WB) and polymerase chain reaction (PCR) methods as confirmatory tests. We conducted a systematic review of the different techniques used in the diagnosis of HTLV-1 infection. Materials and methods Our search was limited to original papers in the English language from 2010 to 2018 using several databases including Pubmed, Scopus, Google Scholar, Iranmedex, and Scientific Information Database. A manual search of references provided in the included papers was also performed. Results Of 101 electronically searched citations, 43 met the inclusion criteria. ELISA is commonly used for qualitative and screening detection, and WB and PCR techniques are used to confirm infection. Conclusion Among all the reported methods for detection of HTLV-1, only serological and molecular tests are used as the most common technical assays for HTLV-1. The ELISA assay, without a confirmatory test, has several limitations and affect the accuracy of the results. Owing to the prevalence of HTLV-1 and limitations of the current detection methods, further evaluation of the accuracy of these methods is needed. There are new opportunities for applying novel technological advances in microfluidics, biosensors, and lab-on-a-chip systems to perform HTLV-1 diagnostics.

Background: Neurological diseases have become an obvious challenge due to insufficient therapeutic intervention. Therefore, novel drugs for various neurological disorders are in desperate need. Recently, compelling evidence has demonstrated that chemokine receptor CXCR3, which is a G protein-coupled receptor in the CXC chemokine receptor family, may play a pivotal role in the development of neurological diseases. The aim of this review is to provide evidence for the potential of CXCR3 as a therapeutic target for neurological diseases. Methods: English journal articles that focused on the invovlement of CXCR3 in neurological diseases were searched via PubMed up to May 2017. Moreover, reference lists from identified articles were included for overviews. Results: The expression level of CXCR3 in T cells was significantly elevated in several neurological diseases, including multiple sclerosis (MS), glioma, Alzheimer’s disease (AD), chronic pain, human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and bipolar disorder. CXCR3 antagonists showed therapeutic effects in these neurological diseases. Conclusion: These studies provided hard evidence that CXCR3 plays a vital role in the pathogenesis of MS, glioma, AD, chronic pain, HAM/TSP and bipolar disorder. CXCR3 is a crucial molecule in neuroinflammatory and neurodegenerative diseases. It regulates the activation of infiltrating cells and resident immune cells. However, the exact functions of CXCR3 in neurological diseases are inconclusive. Thus, it is important to understand the topic of chemokines and the scope of their activity in neurological diseases.

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects T lymphocytes. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an intractable neurodegenerative disease caused by HTLV-1 infection just like adult T cell leukemia/lymphoma (ATL) is, developing in a fraction of infected individuals. Here, we review the update information about the new drug development and therapeutic algorithm of HAM/TSP based on the resent research achievement in molecular pathogenesis and biomarkers.

Background: Physical therapy has positive results in people with tropical spastic paraparesis (TSP). However, mobility and distance from rehabilitation centers limit the participation in outpatient programs. Objective: To evaluate the impact of a home exercise program on the posture and functional mobility of people with TSP. Methods: A randomized controlled trial comparing three groups of people who performed guided exercises from a guidebook for six months: supervised (SG), unsupervised (WG), and control (CG). Primary outcomes: postural angles (SAPO®) and functional mobility (TUG). Secondary outcomes: gait parameters (CVMob®). Results: The protocol described in the guidebook improved postural angles and functional mobility. There were also positive gait parameter effects (p

Human T-lymphotropic virus type-1 (HTLV-1) is a retrovirus that causes the neurological disorder HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP) and/or adult T-cell leukemia/lymphoma (ATLL). Iran is one of the endemic regions of the HTLV-1 in the Middle East. To infer the origin of the virus in Iran and to follow the movements of human population and routes of virus spread to this country, phylogenetic and phylodynamic analyses were performed. To this purpose, the long terminal repeat (LTR) region of HTLV-1 was used. New LTR sequences were obtained from 100 blood samples which infected with HTLV-1. Moreover, all Iranian LTR sequences which have been reported so far, were obtained from GenBank database. Sequences were aligned and maximum-likelihood and Bayesian tree topologies were explored. After identification of Iranian specific cluster, molecular-clock and coalescent models were used to estimate time to the most recent common ancestor (tMRCA). Bayesian Skyline Plots (BSP), representing population dynamics HTLV-1 strains back to the MRCA, were estimated using BEAST software. Phylogenetic analysis demonstrated that the Iranian, Kuwaiti, German, Israelite and southern Indian isolates are located within the widespread “transcontinental” subgroup A clade of HTLV-1 Cosmopolitan subtype a. Molecular clock analysis of the Iranian cluster dated back their respective tMRCA to be 1290 AC with a 95% HPD confidence intervals (918, 1517). BSPs indicated a rapid exponential growth rate in the effective number of infections prior the 15th century. Our results support the hypothesis of a multiple introductions of HTLV-1 into Iran with the majority of introductions occurring in prior the 15th century, at the same time the Mongol invasion of Iran. Our results further suggest that HTLV-1 introduction into Iran was facilitated by the commercial/migratory linkage as known as the ancient Silk Road which linked China to Antioch (now in Turkey).

The objective of this study is to describe the chronic pain characteristics in individuals infected with human T cell lymphotropic virus type 1 (HTLV-1) per subgroup (asymptomatic, oligosymptomatic, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)) compared with controls with chronic pain without HTLV-1. This is a cross-sectional study investigating associations between pain profile, psychopathological symptoms, and quality of life. Individuals infected with HTLV-1 refer high-intensity pain compared with controls, with more severe characteristics being present in oligosymptomatic and HAM/TSP individuals. Oligosymptomatic individuals have a tendency of diffuse and frequent pain, mainly in the head/neck region and more depressive symptoms, resembling nociplastic pain. Neuropathic pain was localized in the lower limbs in all infected groups, worse in HAM/TSP individuals, and associated with a worse perception of quality of life. Pain was associated to higher levels of TNF-alpha and interferon-gamma. HTLV-1 pain is generally more severe when compared with other chronic pain syndromes, being present mainly in the lower limbs. Certain characteristics are typical, depending on the affected group. Oligosymptomatic and HAM/TSP individuals present more diffuse pain, with higher intensity and greater impact in quality of life. Increased levels of inflammatory cytokines are associated with HTLV-1-related pain.

Human T cell leukemia virus type 1 (HTLV-1) is a human retrovirus that is associated with two main diseases: HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukemia/lymphoma (ATL). Chemokines are highly specialized groups of cytokines that play important roles in organizing, trafficking, homing, and in the migration of immune cells to the bone marrow, lymphoid organs and sites of infection and inflammation. Aberrant expression or function of chemokines, or their receptors, has been linked to the protection against or susceptibility to specific infectious diseases, as well as increased the risk of autoimmune diseases and malignancy. Chemokines and their receptors participate in pathogenesis of HTLV-1 associated diseases from inflammation in the central nervous system (CNS) which occurs in cases of HAM/TSP to T cell immortalization and tissue infiltration observed in ATL patients. Chemokines represent viable effective prognostic biomarkers for HTLV-1-associated diseases which provide the early identification of high-risk, treatment possibilities and high-yielding clinical trials. This review focuses on the emerging roles of these molecules in the outcome of HTLV-1-associated diseases.

Although human T-cell lymphotropic virus type-1 (HTLV-1) was the first retrovirus among human pathogens to be identified, insufficient information on the pathogenesis of HTLV-1 infection means that no precise mechanism has yet been provided for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Based on previous studies, it was found that apoptosis and inflammation stimulation were among the most important mechanisms underlying HAM/TSP. The present study provides an in-silico analysis of the microarray data related to HAM/TSP patients. Expression changes of the genes responsible for cytotoxicity and apoptosis processes of HAM/TSP patients and asymptomatic carriers were investigated. Expression of the genes involved in cytotoxicity and apoptosis in HAM/TSP patients was decreased; hence, a model was proposed indicating that the spread of immune responses in HAM/TSP may be due to expression of HTLV-1 virulence factors and the resistance of HTLV-1-infected cells to apoptosis.

Background HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive neurological and inflammatory disease, associated with HTLV-1 infection. HAM/TSP neurological disease is a consequence of an inflammatory reaction, and adaptive immune responses, through the secretion of anti-inflammatory and pro-inflammatory cytokines, play an important role in the outcome of infection and disease progression. Studies addressing the association between cytokines functional single nucleotide polymorphisms and HAM/TSP development are scarce. Methods The genetic polymorphisms of cytokine genes were evaluated in HAM/TSP patients (n = 68) and in asymptomatic HTLV-1 positive carriers (n = 83) from Rio de Janeiro, Brazil, in a case-control study. HTLV-1 infected patients were genotyped for SNPs in five cytokine genes: TNFA-308G/A, IL6-174G/C, IFNG + 874 T/A, TGFB at the codons + 10 T/C and + 25G/C, IL10-592C/A and -819C/T, and -1082A/G and proviral load (PVL) was quantified. Associations between genotypes, haplotypes, clinical outcome and pro viral load were evaluated. Results Lack of association between the cytokine polymorphisms and disease outcome was observed. The genotypes TNFA-308GG, IL6-174GG/GC, IL10-592AA and -819CC and TGFb1 high producers phenotypes were correlated with higher PVL in HAM/TSP patients versus asymptomatic carriers. Conclusions We did not observe association between cytokine polymorphisms and risk for HAM/TSP development in Brazilian HTLV-1 infected individuals, regardless of differences in PVL between HAM/TSP versus asymptomatic carriers in specific cytokine polymorphisms.

Introduction Human T-lymphotropic virus (HTLV)-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disorder that mostly affects women. This disease is characterized by a progressive loss of motor function and disruptions in sensory function in the lower limbs. HTLV-1 is also associated with isolated neurologic dysfunctions, overactive bladder, and erectile dysfunction. The occurrence of sexual dysfunction in HTLV-1–infected women remain unclear. Aim To investigate associations between HTLV-1 infection and sexual dysfunction in both asymptomatic infected women and those diagnosed with HAM/TSP compared with uninfected women. Methods HTLV-1–infected and uninfected women were assessed for sexual dysfunction using the Female Sexual Function Index instrument. Sexual dysfunction was considered if global Female Sexual Function Index scores were Results HTLV-1–infected women (n = 72; 57 asymptomatic; 15 HAM/TSP) and HTLV-1 uninfected women (n = 49) were evaluated. The overall sexual dysfunction prevalence was 53.7% (65/121), which was higher in the HAM/TSP group (80.0%; adjusted PR 1.89; 95% CI 1.23–2.90) when compared with non-infected individuals (44.9%). Sexual dysfunction was found in 54.4% of the HTLV-1–infected asymptomatic women (PR 1.21; 95% CI 0.82–1.79). Sexual dysfunction was associated with income lower than 1 minimal wage (∼US $300, October 2017) and number of previous birthday. Conclusion The obtained results indicate that sexual dysfunction is associated with HAM/TSP in women infected with HTLV-1 of reproductive age.

The human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus claimed to be aetiologically linked to the adult T-cell leukaemia/lymphoma (ATLL) and associated myelopathy/tropical spastic paraparesis (HAM/TSP) besides other minor pathologies. HTLV-1 infection is worldwide distributed, despite its heterogeneous prevalence. Environmental factors and host-genetic background are very likely to determine the epidemiological profile of HTLV-1 prevalence and related disease confinement in distinct human ethnic populations and geographical coordinates, which raises the question if the virus is a real pathogen or a runaway well-organized packed genome of a burden host cell near death process. New methodological approaches need to be proposed and applied in order to prove or discard the hypotheses emerged in the present review.

Introduction The human T-cell lymphotropic virus type 1 (HTLV-1) is aetiologically linked to myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukaemia (ATL) besides other less incident pathologies, while the type 2 has not been definitively linked to any diseases. Objectives To determine the HTLV-1/2 seroprevalence in two Brazilian communities in northern Brazil. Methods In 2010 and 2015, HTLV-1/2 serological surveys were carried out in the Oiapoque county at the Brazilian border with French Guiana and in Santa Cruz do Arari, Marajó Island. Serum and breast-milk samples from 317 women (pregnant, lactating and non-pregnant non-lactating) resident in the Oiapoque county, together with serum samples from 217 females and 70 males living in Santa Cruz do Arari county, were twice screened by two distinct commercial immunoassay methods for antibodies to HTLV-1/2. Seroreactivity was confirmed by a commercial Western blot technique. Participants were interviewed for data concerning their health, socioeconomic and educational status. Results None of the Oiapoque women, mostly young and descendants of migrants, had antibodies to HTLV-1/2, despite the high HTLV-1 prevalence in neighbouring French Guiana and Caribbean Islands, while five females and three males living in Santa Cruz do Arari county were HTLV-1 infected as confirmed by Western blot testing. In contrast, the Santa Cruz do Arari community lives in relative isolation and is descended mostly from black African people with high consanguinity. Conclusion Despite the proximity between Oiapoque and Santa Cruz do Arari counties, ethnic, age differences, community isolation and consanguinity may explain the distinct HTLV-1/2 epidemiology in these areas of northern Brazil.

Background Human T-cell lymphotropic virus type-1 (HTLV-1) may cause severe diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and infective dermatitis associated with HTLV-1 (IDH). The clinical characteristics and progression of 25 early onset HAM/TSP associated or not to IDH were described. Methods Following-up 37 IDH patients with neurological examinations, 54% developed HAM/TSP. To these cases were added 5 cases of juvenile HAM/TSP. The patients were HTLV-1+ and were submitted to dermatological and neurological examinations. Diagnosis of HAM/TSP was performed according to Osame et al (1990) and Castro-Costa et al (2006) criteria. Results Twenty-one patients were classified as definite HAM/TSP by both criteria, 3 as probable HAM/TSP by Osame et al, and another as probable HAM/TSP according to Castro-Costa et al Median age at onset of neurological manifestations was 9 years for the IDH/HAM/TSP group and 16 years for the HAM/TSP group (P = .045). In 12 patients, the onset of neurological manifestations occurred when they were less than 10 years of age. In the group IDH/HAM/TSP, the neurological symptoms always begun during the period of activity of IDH. The progression of HAM/TSP evaluated in 17 cases was heterogeneous, and 3 had rapid progressive course. Conclusions The juvenile HAM/TSP may occur very early and also presents marked female predominance. Progression of IDH to HAM/TSP before 19 years of age is frequent (54%). Rapid progressive form may also occur in early HAM/TSP. As juvenile IDH and HAM/TSP are due to vertical transmission through breastfeeding, it is very important to avoid this pathway of infection.

INTRODUCTION: Human T-cell lymphotropic virus type-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) may lead to reduced functional mobility and balance. It is important to establish specific parameters that identify these changes and predict the risk of falls in these patients. The aim was to compare balance, functional mobility, and occurrence of falls among patients with and without HAM/TSP and to suggest values to predict the risk of falls in these patients. METHODS: A cross-sectional study in patients with and without HAM/TSP involved balance assessments based on the berg balance scale (BBS) and functional mobility evaluation based on the timed up and go (TUG) test. From reports of falls, the sensitivity, specificity, and best cutoff points for the risk of falls assessed by these instruments were established using the receiver-operating characteristic (ROC) curve; 5% alpha was considered. RESULTS: We selected 42 participants: 29 with HAM/TSP and 13 without HAM/TSP. There was a statistically significant difference in the occurrence of falls, balance, and functional mobility between the groups (p

The main clinical feature of human T cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is slowly progressive spastic paraparesis with bladder dysfunction. HAM/TSP is induced by chronic inflammation in the spinal cord, mainly the lower thoracic cord. A long-standing bystander mechanism, such as the destruction of surrounding tissues by the interaction between infiltrated Th1-like, HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ cytotoxic T cells (CTL), is probably critical for the induction of chronic inflammation. Although the HTLV-1-infected CD4+ T cells in HAM/TSP appear to play a crucial role in the initial pathogenesis of HAM/TSP, the exact mechanisms of how these cells acquire their function as the first responders in the pathogenesis of HAM/TSP still remain unresolved. Herein, we propose the importance of the activation of both outside-in signals from integrin signaling and inside-out signals for integrin signaling in the HTLV-1-infected CD4+ T cells of HAM/TSP patients.

Background: Infection 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. Objective: To 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 methods: From 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. Results: From 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

Resumen Introducción. El virus linfotrópico humano de células T (HTLV) es un retrovirus del cual se conocen varios tipos, entre ellos el HTLV-I y el HTLV-II, los cuales son de importancia clínica por ser los causantes de diferentes enfermedades, como la leucemia y el linfoma de células T del adulto, la paraparesia espástica tropical y la mielopatía asociada al HTLV. Objetivo. Obtener la prevalencia de las reacciones presuntiva y confirmatoria de los virus HTLV-I y HTLV-II en los donantes del Banco de Sangre del Hospital Pablo Tobón Uribe de Medellín, entre el 2014 y el 2015. Materiales y métodos. La información se obtuvo de la base de datos del Banco de Sangre del Hospital Pablo Tobón Uribe. Se analizaron la edad, el sexo y el lugar de procedencia y de residencia de los donantes, así como la reacción en la prueba de tamización (ELISA) y en la prueba confirmatoria (inmunoblot). Resultados. La población de donantes estudiados incluyó a 6.275 hombres y 8.148 mujeres, para un total de 14.423 donantes reclutados entre el 1° de marzo de 2014 y el 30 de junio de 2015. De ellos, 25 resultaron positivos para HTLV-I o HTLV-II en la prueba de tamización (ELISA). En la prueba confirmatoria (inmunoblot), nueve (36 %) pacientes fueron positivos para el HTLV-I o HTLV-II , y de ellos ocho (32 %) lo fueron para el HTLV-I y uno (4 %) para el HTLV-II; la seroprevalencia global fue de 0,06 % (IC95% 0,10-0,25). Conclusiones. Los hallazgos del estudio concordaron con los de estudios similares en áreas no endémicas del país y con los de los estudios consultados a nivel internacional. Abstract Introduction: The human-T cell lymphotropic virus is a retrovirus with various types known so far. HTLV-I and HTLV-II are of clinically importance as they cause different diseases such as adult T-cell leukemia/lymphoma, tropical spastic paraparesis, and human T-lymphotropic virus type I-associated myelopathy (HAM). Objective: To estimate the prevalence of presumptive and confirmatory reactivity to HTLV-I/II in blood donors of Hospital Pablo Tobón Uribe Blood Bank between 2014 and 2015. Materials and methods: The information was obtained from the Hospital Pablo Tobón Uribe Blood Bank database. We analyzed age, sex, place of origin, and place of residence of donors, and the reactivity using the screening test (ELISA) as well as the confirmatory test (immunoblot). Results: The donor population studied included 6,275 men and 8,148 women, for a total of 14,423 donors recruited between March 1, 2014, and June 30, 2015. Of all tested donors, 25 were positive for HTLV-I/II by the screening test (ELISA). After performing the confirmatory test (immunoblot), only nine patients were positive for HTLV-I/II (36%), of whom eight were reactive to HTLV-I (32%) and one to HTLV-II (4%), for a global seroprevalence of 0.06% (CI 95%: 0.10-0.25). Conclusions: Our findings were consistent with those found in similar studies in non-endemic areas of the country and with those from studies at international level reported in the literature.

Background Human T-lymphotropic virus type 1 (HTLV-1) is the main cause of adult T cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The aim of this study was to evaluate the dysregulation of immune genes that may be involved in the pathogenesis of ATLL using microarray datasets. Method The gene expression profiles of ATLL cases (GSE19080) were obtained from GEO database. Next, the quality and reliability of data were evaluated by MetaQC, and the expression data in each group were normalized by affy package. Subsequently, the R package MetaDE was applied for the analysis of differentially expressed genes (DEGs). Using STRING database, protein-protein interaction network (PPIN) was constructed for hub DEGs. Finally, online servers including STRING, Enrichr, and KEGG pathway were applied for gene enrichment and interpretation of the results. Results 65 significant hub DEGs were divided in three groups, normal health, asymptomatic carrier and ATLL patients. The PPIN analysis between hub DEGs was carried out by STRING. Enrichment analysis revealed that the hub DEGs were involved in various pathways such as apoptosis, proliferation of T cell, Ras signaling, MAPK signaling, NF-κB signaling, integrin signaling, P53 signaling, angiogenesis, tissue invasion, and DNA damage process. Conclusion According to the present study, HTLV-1 appears to cause inflammation by enhancing cell proliferation. During the HTLV-1 infection, dysregulation of immune genes such as IL-10, TGF-β, JAK, BCL2, etc. result in immortalization of HTLV-1-infected CD4+ T cells, and eventually progression to ATLL.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neuroinflammatory disease related to human T lymphotropic virus type 1 (HTLV-1) infection. Interferon type III (IFN-λ), which includes IL28, IL29, and IL28R, and affects the outcome of viral infections, might be complicated in the progression of HAM/TSP. Here, we investigated the host-virus interactions in the manifestation of HAM/TSP, using IL28B, IL29, IL28R, HTLV-1 Tax, HTLV-1 basic leucine zipper factor (HBZ), and proviral load (PVL). The study groups consisted of 20 patients with HAM/TSP, 20 asymptomatic HTLV-1 carriers (ACs), and 20 healthy controls (HCs). The means of PVL, Tax, and HBZ gene expressions in the HAM/TSP group (p = 0.004, 0.006, and < 0.0001, respectively) were significantly higher than in the AC group. The comparison of IL28B, IL29, and IL28R expression in the HAM/TSP, AC, and HC groups revealed no significant difference between the first 2, but lower concentrations in the HCs (IL28B: p = 0.03, 0.01; IL29: p = 0.07, 0.01; and IL28R: p < 0.0001, respectively). In the HAM/TSP group, correlations were seen between Tax and HBZ (R = 0.61, p = 0.004) and between Tax and IL29 (R = 0.45, p = 0.04). Negative correlations were observed between Tax and IL28B (R = –0.49, p = 0.02) and between HBZ and IL28R (R = –0.43, p = 0.06). In the ACs, an inverse correlation was found between Tax and IL28B (R = –0.42, p = 0.06). These findings suggest that IL29, IL28B, and IL28R interfere in the infection of HAM/TSP, mainly via Tax activation.

Rationale: Adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are caused by HTLV-1, but the coexistence of both disorders is rare. The estimated incidence is approximately 3%. Patient concerns: A 54-year-old man was unable to stand up because of spastic paraparesis 1 month after the onset. He developed lymphadenopathy in the left supraclavicular fossa 5 months after the onset. The spastic paraplegia and sensory symptoms below the thoracic spinal cord level worsened. Diagnoses: Both blood and cerebrospinal fluid (CSF) tests were positive for anti-HTLV-1 antibodies. The patient was diagnosed with rapidly progressive HAM/TSP. He was also diagnosed with lymphoma-type ATL by the biopsy specimen of the lymph node. CSF examination at the time of symptom exacerbation showed abnormal lymphocytes, suggesting central infiltration of the ATL in the central nervous system. Interventions: Methylprednisolone pulse therapy and oral prednisolone maintenance therapy were administered for rapidly progressive HAM/TSP. Intrathecal injection of methotrexate was administered for the suggested central infiltration of the ATL. Outcomes: Methylprednisolone pulse therapy and intrathecal injection of methotrexate did not improve the patient's exacerbated symptoms. Five months later, clumsiness and mild muscle weakness of the fingers appeared, and magnetic resonance imaging showed swelling of the cervical spinal cord. Clonality analysis showed monoclonal proliferation only in the DNA of a lymph node lesion, but not in the CSF and peripheral blood cells. Lessons: This was a case of rapidly progressive HAM/TSP associated with lymphoma-type ATL that was refractory to steroids and chemotherapy. The pathogenesis was presumed to involve ATL cells in the brain and spinal cord because of the presence of abnormal lymphocytes in the CSF, but DNA analysis could not prove direct invasion. This case suggests that when we encounter cases with refractory HAM/TSP, it should be needed to suspect the presence of ATL in the background.

HAM/TSP patients experience impaired functional capacity. The use of categorical scales to accurately describe motor ability in these patients has been questioned.Aim: To evaluate the functional capacity of HAM/TSP patients by using the individual tests comprising the GDLAM protocol.Methods: Cross sectional study carried out in the CHTLV, Salvador, Brazil. Functional capacity was evaluated using the tests of the GDLAM protocol (timed 10-minute walk, getting up from a sitting position, rising from a prone position, getting up from a chair, and moving around the house). Functional classifications were made by comparing patient performance to that of uninfected control individuals.Results: Twenty-four HAM/TSP and 25 healthy individuals were enrolled. Only 75% HAM/TSP patients completed the GDLAM protocol. Six patients failed to perform the RPP test. Timed measurements were significantly higher in the HAM/TSP patients in comparison to uninfected controls.Conclusion: The use of alternative methods, such as the individual tests comprising the GDLAM protocol, may more accurately assess motor function in HAM/TSP patients.

The human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of adult T cell leukemia/lymphoma (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4+T cells are the main target of HTLV-1, but other cell types are known to be infected, including immature lymphocytes. Developing T cells undergo differentiation in the thymus, through migration and interaction with the thymic microenvironment, in particular with thymic epithelial cells (TEC) the major component of this three dimensional meshwork of non-lymphoid cells. Herein, we show that TEC express the receptors for HTLV-1 and can be infected by this virus through cell-cell contact and by cell-free virus suspensions. The expression of anti-apoptosis, chemokine and adhesion molecules genes are altered in HTLV-1-infected TEC, although gene expression of antigen presentation molecules remained unchanged. Furthermore, HTLV-1-infected TEC transmitted the virus to a CD4+ T cell line and to CD4+ T cells from healthy donors, during in vitro cellular co-cultures. Altogether, our data point to the possibility that the human thymic epithelial cells play a role in the establishment and progression of HTLV-1 infection, functioning as a reservoir and transmitting the virus to maturing CD4+ T lymphocytes, which in turn will cause disease in the periphery.

Background:Chemokine (C-C motif) ligand 1 (CCL1) is produced by activated monocytes/ macrophages and T-lymphocytes, and acts as a potent attractant for Th2 cells and a subset of T-regulatory (Treg) cells. Previous reports have indicated that CCL1 is overexpressed in adult T-cell leukemia cells, mediating an autocrine anti-apoptotic loop. Because CCL1 is also known as a potent chemoattractant that plays a major role in inflammatory processes, we investigated the role of CCL1 in the pathogenesis of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Results:The results showed that: (1) CCL1 was preferentially expressed in HAM/TSP-derived HTLV-1-infected T-cell lines, (2) CCL1 expression was induced along with Tax expression in the Tax-inducible T-cell line JPX9, (3) transient Tax expression in an HTLV-1-negative T-cell line activated the CCL1 gene promoter, (4) plasma levels of CCL1 were significantly higher in patients with HAM/TSP than in HTLV-1-seronegative patients with multiple sclerosis and HTLV-1-infected asymptomatic healthy carriers, and (5) minocycline inhibited the production of CCL1 in HTLV-1-infected T-cell lines. Conclusions:The present results suggest that elevated CCL1 levels may be associated with the pathogenesis of HAM/TSP. Although further studies are required to determine the in vivo significance, minocycline may be considered as a potential candidate for the long-term treatment of HAM/TSP via its anti-inflammatory effects, which includes the inhibition of CCL1 expression., 論文

Objective Previous work measures spinal cord thinning in chronic progressive myelopathies, including human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Quantitative measurements of spinal cord atrophy are important in fully characterizing these and other spinal cord diseases. We aimed to investigate patterns of spinal cord atrophy and correlations with clinical markers. Methods Spinal cord cross-sectional area was measured in individuals (24 healthy controls [HCs], 17 asymptomatic carriers of HTLV-1 (AC), 47 HAM/TSP, 74 relapsing-remitting MS [RRMS], 17 secondary progressive MS [SPMS], and 40 primary progressive MS [PPMS]) from C1 to T10. Clinical disability scores, viral markers, and immunological parameters were obtained for patients and correlated with representative spinal cord cross-sectional area regions at the C2 to C3, C4 to C5, and T4 to T9 levels. In 2 HAM/TSP patients, spinal cord cross-sectional area was measured over 3 years. Results All spinal cord regions are thinner in HAM/TSP (56 mm2 [standard deviation, 10], 59 [10], 23 [5]) than in HC (76 [7], 83 [8], 38 [4]) and AC (71 [7], 78 [9], 36 [7]). SPMS (62 [9], 66 [9], 32 [6]) and PPMS (65 [11], 68 [10], 35 [7]) have thinner cervical cords than HC and RRMS (73 [9], 77 [10], 37 [6]). Clinical disability scores (Expanded Disability Status Scale [p = 0.009] and Instituto de Pesquisas de Cananeia [p = 0.03]) and CD8+ T-cell frequency (p = 0.04) correlate with T4 to T9 spinal cord cross-sectional area in HAM/TSP. Higher cerebrospinal fluid HTLV-1 proviral load (p = 0.01) was associated with thinner spinal cord cross-sectional area. Both HAM/TSP patients followed longitudinally showed thoracic thinning followed by cervical thinning. Interpretation Group average spinal cord cross-sectional area in HAM/TSP and progressive MS show spinal cord atrophy. We further hypothesize in HAM/TSP that is possible that neuroglial loss from a thoracic inflammatory process results in anterograde and retrograde degeneration of axons, leading to the temporal progression of thoracic to cervical atrophy described here. Ann Neurol 2017;82:719–728.

The human T cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 infected individuals have increased susceptibility to Mycobacterium tuberculosis infection but the influence of tuberculosis (TB) on the course of HTLV-1 infection is unknown. The aim of this study was to evaluate the influence of TB on immunological, virologic, and neurologic features of HTLV-1 infection. This is a retrospective analysis of individuals enrolled in a cohort study from an HTLV-1 clinic who were evaluated for past or latent tuberculosis (LTB) and classified clinically as HTLV-1 carriers, probable HAM/TSP and definite HAM/TSP. Spontaneous cytokine production (interferon-gamma [IFN-γ], tumor necrosis factor [TNF], and interleukin[IL]-10), serum chemokines (CXCL9 and CXCL10) and HTLV-1 proviral load were evaluated. Of 172 participants, 64 did not have histories of TB (TB- group), 81 had LTB and 27 had TB in the past (TB+ group). In the TB+ group, there was a higher frequency of HAM/TSP patients (35%) than in HTLV-1 carriers (10%) (OR = 3.8, p = .0001). HAM/TSP patients with histories of TB had higher IFN-γ/IL-10 and TNF/IL-10 ratios when compared with HAM/TSP patients without histories of TB. There were no differences in serum chemokine production and proviral load across TB groups stratified on HTLV-1 clinical status. In conclusion, TB may influence the development of HAM/TSP, and patients with these two diseases have an impairment in the modulation of immune response.

Since hepatitis C virus (HCV) and human T-lymphotropic virus (HTLV) share transmission routes, dual infection could be frequent. In Spain, HTLV underdiagnosis is highlighted by the high proportion of patients presenting either with tropical spastic paraparesis or adult T cell leukemia at first diagnosis. We examined whether the renewed efforts for expanding HCV testing may provide a sentinel population that might selectively be targeted to unveil asymptomatic HTLV carriers. The presence of anti-HTLV antibodies was examined in 3,838 consecutive individuals with reactive HCV serology attended during the last 3 years at 13 hospitals distributed across the Spanish geography. Overall 71% were male, and the median age was 41 years old. Foreigners represented 9% of the study population. A total of 50 individuals (1.3%) were seroreactive for HTLV, being 30 confirmed as HTLV-2 and 2 as HTLV-1 (0.12%). The remaining 18 had indeterminate Western blot patterns. Most individuals with HTLV-2 and HTLV indetermi...

Background Erectile dysfunction (ED) occurs in more than 50% of patients with human T-cell lymphotropic virus type 1 (HTLV-1) infection. In the general population, atherosclerosis is the main risk factor related to ED. Aim To compare the contribution of neurologic disorders from HTLV-1 with that of atherosclerosis as risk factors for ED in men with HTLV-1. Methods In this cross-sectional study, men 18 to 70 years old with HTLV-1 were classified into one of two groups according to the presence or absence of ED. They were compared for obesity, waist circumference, dyslipidemia, metabolic syndrome, diabetes mellitus, high blood pressure, and neurologic manifestations. Comparisons between proportions were performed using the χ2 or Fisher exact test. Logistic regression analysis was performed to identify predictors of ED. Subjects with HTLV-1 were classified into three groups based on Osame's Disability Motor Scale and the Expanded Disability Status Scale: (i) HTLV-1 carriers; (ii) probable HTLV-1–associated myelopathy or tropical spastic paraparesis; and (iii) definitive HTLV-1–associated myelopathy or tropical spastic paraparesis. The International Index of Erectile Function was used to determine the degree of ED. Results In univariate logistic regression, age older 60 years (P = .003), diabetes mellitus (P = .042), and neurologic disease (P < .001) were associated with ED. In the multivariate model, the odds of ED was highest in patients with neurologic disease (odds ratio = 22.1, 95% CI = 5.3–92.3), followed by high blood pressure (odds ratio = 6.3, 95% CI = 1.4-30.5) and age older than 60 years (odds ratio = 4.6, 95% CI = 1.3–17.3). Clinical Implications In men infected with HTLV-1, neurologic dysfunction is a stronger predictor of ED than risk factors for atherosclerosis. Strengths and Limitations The small number of patients limited the power of the statistical analysis, but clearly neurologic manifestations had a greater association with ED than risk factors for atherosclerosis, and there was no association between metabolic syndrome and severity of ED. Conclusion Neurologic impairment is the major cause of ED in individuals infected with HTLV-1 and risk factors for atherosclerosis did not have a strong relation with ED in this population.

Purpose. Chemokines are important in the immune response against viral infections, and may play a role in human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) pathogenesis. Polymorphisms in the Duffy antigen receptor for chemokines (DARC), such as rs12075 (A>G; FY*B>FY*A) and rs281477 (−46T>C; GATA-1 box) may influence circulating concentrations of proinflammatory chemokines. We investigate whether Duffy genotypes influence the HTLV-1 proviral load (PVL) level, HTLV-1 infection outcome and chemokine concentrations in HTLV-1 asymptomatic carriers (AC=162), HAM/TSP patients (HAM=135) and seronegative individuals (SN=71). Methodology. Quantification of plasmatic IL8, CCL2 and CCL5 were performed by flow cytometry and Duffy genotypes were investigated by real-time PCR. HTLV-1 PVL was quantified in peripheral blood. To control for spurious association, individual ancestry profiles in AC and HAM groups were investigated. Results/Key findings. PVL and IL8 level were significantly higher in the HAM group than in the AC group, but were not associated with Duffy genotypes. The highest CCL2 and CCL5 levels were seen in the SN group, and there was no difference when comparing the infected groups. The level of CCL5 was not associated with Duffy genotypes. The polymorphism −46 C/C that abrogates the DARC expression on the erythrocytes was significantly associated with lower levels of CCL2, neutrophil and white blood cell (WBC) counts in HTLV-1-infected individuals. Conclusion. We conclude that although the Duffy null genotype was associated with leukopenia, neutropenia and lower levels of CCL2, the data do not suggest the influence of Duffy genotypes on the neurologic outcome of HTLV-1 infection, but may be a confounding factor in comparison HTLV-1-infected populations with different ancestries, especially when defining inflammatory biomarkers.

Approximately 5% of human T-cell leukemia virus type 1 (HTLV-1)-infected individuals will develop one of the HTLV-1-related diseases, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T-cell leukemia. However, the mechanisms responsible for the appearance of symptoms have not been fully clarified. It is believed that viral factors, host genetic and epigenetic mechanisms are implicated in this process. Studies have shown the involvement of histone methyltransferases in retrovirus infection, but no study observed their expression in HTLV-1-infected patients. Among them, euchromatic histone-lysine N-methyltransferase (EHMT)-1 and EHMT-2 were related to retroviral latency in HIV-1 infection. We investigated whether histone methyltransferases EHMT1 and EHMT2 exert any influence on HAM/TSP development by assessing their expression levels in CD4+ T-cells from HTLV-1-infected patients. CD4+ T-cells were immunomagnetically isolated from peripheral blood mononuclear cells of HTLV-1-infected or non-infected individuals and the expression levels of EHMT1 and EHMT2 were determined by RT-qPCR. We observed that EHMT2 was negatively regulated in HTLV-1 asymptomatic carriers compared to non-infected individuals. No difference was observed for EHMT1. These results suggest that EHMT2 downregulation in CD4+ T-cells may be linked to a protection mechanism against the development of HAM/TSP.

Key Points The therapeutic efficacy of the AZT and IFN combination in ATL presumably reflects the inhibition of RT-related functions. HTLV-1–RT activity from short-term cultured PBMCs may represent a predictive correlate of clinical response to AZT/IFN in ATL patients.