• Humans
• Gabon/epidemiology
• Middle Aged
• Adult
• HTLV-I Infections/epidemiology
• HTLV-I Infections/virology
• HTLV-I Infections/diagnosis
• Male
• Female
• Human T-lymphotropic virus 1/genetics
• Human T-lymphotropic virus 1/isolation & purification
• Cross-Sectional Studies
• Inpatients
• Prevalence
• Aged

• Glucocorticoid
• HTLV1
• Myelopathy
• Paraparesis
• Treatment

• HTLV-1
• HTLV-1 associated myelopathy/tropical spastic paraparesis
• human T lymphotropic virus 1
• postpartum
• pregnancy

• Adult
• Female
• Humans
• Pregnancy
• Disease Progression
• HTLV-I Infections/complications
• Human T-lymphotropic virus 1
• Paraparesis, Tropical Spastic/virology
• Pregnancy Complications, Infectious/virology

• CB1 receptor
• CB2 receptor
• Cannabinoids
• HTLV‐1‐associated myelopathy/tropical spastic paraparesis
• Human T-lymphotropic virus 1

• Humans
• Male
• Female
• Receptor, Cannabinoid, CB1/metabolism
• Adult
• Receptor, Cannabinoid, CB2/metabolism
• Paraparesis, Tropical Spastic
• Middle Aged
• Human T-lymphotropic virus 1
• Gene Products, tax/metabolism
• Basic-Leucine Zipper Transcription Factors/metabolism
• Viral Load
• Retroviridae Proteins/metabolism

• CXCL10
• Human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis
• KW-0761
• Mogamulizumab
• Neopterin
• Osame motor disability score

• Humans
• Double-Blind Method
• Antibodies, Monoclonal, Humanized/administration & dosage
• Male
• Middle Aged
• Female
• Paraparesis, Tropical Spastic/drug therapy
• Paraparesis, Tropical Spastic/cerebrospinal fluid
• Adult
• Aged
• Neopterin/cerebrospinal fluid
• Human T-lymphotropic virus 1/drug effects
• Chemokine CXCL10/cerebrospinal fluid
• Viral Load/drug effects
• Treatment Outcome

• Kyowa Kirin

• Brazil
• HTLV-1-associated myelopathy
• early stage
• incidence
• surrogate markers

• Humans
• Female
• Middle Aged
• Male
• Incidence
• Aged
• Adult
• Human T-lymphotropic virus 1/isolation & purification
• Paraparesis, Tropical Spastic/epidemiology
• Paraparesis, Tropical Spastic/virology
• Paraparesis, Tropical Spastic/diagnosis
• Carrier State/epidemiology
• Carrier State/virology
• HTLV-I Infections/epidemiology
• HTLV-I Infections/complications
• Viral Load
• Young Adult
• Spinal Cord Diseases/epidemiology
• Spinal Cord Diseases/virology

• Global Health
• HAM/TSP
• HTLV-1

• Adult
• Female
• Humans
• Aged
• Paraparesis, Tropical Spastic/diagnosis
• Paraparesis, Tropical Spastic/therapy
• Paraparesis, Tropical Spastic/complications
• Human T-lymphotropic virus 1
• Quality of Life
• HTLV-I Infections/complications
• HTLV-I Infections/diagnosis
• HTLV-I Infections/therapy
• Risk Factors

• Epidemiology
• HTLV-1
• Myelopathy
• Prenatal screening
• Sexually transmitted infections
• Testing

• Middle Aged
• Humans
• Female
• Paraparesis, Tropical Spastic/epidemiology
• Paraparesis, Tropical Spastic/diagnosis
• Spain/epidemiology
• Leukocytes, Mononuclear
• HTLV-I Infections/epidemiology
• HTLV-I Infections/diagnosis
• Human T-lymphotropic virus 1/genetics
• Viral Load

• Disability evaluation
• Evaluation study
• HTLV-1-associated myelopathy
• Psychometrics

• Humans
• Paraparesis, Tropical Spastic/diagnosis
• Human T-lymphotropic virus 1
• Reproducibility of Results
• Quality of Life
• Communicable Diseases

• 307045/2016-1 Conselho Nacional de Desenvolvimento Científico e Tecnológico

• HAM/TSP
• HTLV-1
• mogamulizumab
• myelopathy
• rash

• Humans
• Female
• Paraparesis, Tropical Spastic/drug therapy
• Human T-lymphotropic virus 1
• Antibodies, Monoclonal, Humanized/adverse effects
• Exanthema
• Viral Load

• R01 MH131194 NIMH NIH HHS
• K23 MH115812 NIMH NIH HHS
• Dalcor Pharmaceuticals

• HAM/TSP
• HTLV-1
• adhesion molecule
• chronic myelitis
• integrin
• matrix metalloproteinases
• small GTPase
• transmigration

• HTLV-1
• HTLV-1-associated myelopathy
• cerebrospinal fluid
• laboratorial diagnosis
• tropical spastic paraparesis

• clinical methods
• clinical therapeutics
• diagnostics
• epidemiology
• human T-cell leukemia virus
• oncogenic virus
• pathogenesis
• public health
• sexually transmitted diseases
• virology

• Adult
• HTLV-I Infections/diagnosis
• HTLV-I Infections/epidemiology
• HTLV-I Infections/prevention & control
• Human T-lymphotropic virus 1
• Humans
• Leukemia-Lymphoma, Adult T-Cell/epidemiology
• Paraparesis, Tropical Spastic/epidemiology
• Paraparesis, Tropical Spastic/pathology
• Public Health

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM) is a neuroinflammatory disease, causing various neurological symptoms, including motor, sensory, and bladder and bowel dysfunctions. This study was designed to reveal the impact of HAM and related symptoms on health-related quality of life (HRQoL).

We analyzed the Short Form-36 (SF-36) and clinical data of 538 patients with HAM registered in the HAM-net, a nationwide patient registry for HAM in Japan. HRQoL was evaluated using the SF-6D (a health state utility value calculated from the SF-36) and eight SF-36 subscales. A general liner model was used to estimate the impact of major HAM-related symptoms, including gait dysfunction, sensory disturbance in the legs (pain and numbness), urinary dysfunction, and constipation, on the SF-6D and SF-36 subscale scores.

The mean age and disease duration were 62.0 and 16.5 years, respectively. Of the patients, 73.2% needed walking aid; 42.7 and 67.1% had leg pain and numbness, respectively; 92.1% had urinary dysfunction; and 77.9% had constipation. The mean SF-6D score was 0.565, which was significantly lower than the national average (0.674 in the 60–69 years age group; p < 0.001), exceeding the minimal important difference (0.05–0.1). All the major symptoms were significantly associated with a decrease in the SF-6D score. The SF-36 subscale scores were significantly lower than the national standard of 50 (p ≤ 0.001), except for mental health (MH). Gait dysfunction was associated with lower scores in physical functioning (PF), limitations on role functioning because of physical health, bodily pain, general health perception (GH), vitality (VT), and social functioning; however, no association was observed between gait dysfunction and limitations on role functioning because of emotional problems and MH. Meanwhile, sensory disturbance in the legs was associated with a decrease in scores in all subscales. Urinary dysfunction was associated with worse PF, GH, VT, and MH. Constipation was associated only with PF.

HRQoL of patients with HAM was worse than that of the general population and was associated with all major symptoms. Thus, patients should be comprehensively managed to achieve better HRQoL.

While bladder dysfunction is observed in the majority of patients with human T cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM), it is also observed in patients who do not fulfill all diagnostic criteria for HAM. These patients are classified as having possible or probable HAM/TSP. However, it remains unclear whether the severity and progression of bladder dysfunction occurs similarly between these two groups.

Compare the severity and evolution of bladder dysfunction in HTLV-1-infected patients with possible and definite HAM/TSP.

The present prospective cohort study followed 90 HTLV-1 patients with possible HAM/TSP and 84 with definite HAM/TSP between April 2011 and February 2019. Bladder dysfunction was evaluated by bladder diary, overactive bladder symptoms scores (OABSS) and urodynamic studies. Bladder dysfunction progression was defined as the need for clean self-intermittent catheterization (CIC).

At baseline, nocturia, urgency and OABSS scores were worse in definite compared to possible HAM/TSP patients. The main urodynamic finding was detrusor overactivity, present in 77.8% of the patients with definite HAM/TSP versus 58.7% of those with possible HAM/TSP (P = 0.05). Upon study conclusion, the cumulative frequency of patients requiring CIC increased in both groups, from 2 to 6 in possible HAM/TSP and from 28 to 44 in definite HAM/TSP patients. The estimated time to need for CIC was 6.7 years (95%CI 6.5–7.0) in the possible HAM/TSP group compared to 5.5 years (95%CI 4.8–6.1) in the definite HAM/TSP group.

Although both groups showed similarities in bladder dysfunction and tended to progress to requiring CIC over time, patients with possible HAM/TSP presented less severe manifestations at baseline and progressed more slowly than those with definite HAM/TSP.

The present prospective cohort study followed 90 HTLV-1 patients with possible HAM/TSP and 84 with definite HAM/TSP between April 2011 and February 2019. Bladder dysfunction was evaluated by bladder diary, overactive bladder symptoms scores (OABSS) and urodynamic studies. Bladder dysfunction progression was defined as the need for clean self-intermittent catheterization (CIC). At baseline, nocturia, urgency and OABSS scores were worse in definite compared to possible HAM/TSP patients. The main urodynamic finding was detrusor overactivity, present in 77.8% of the patients with definite HM/TSP versus 58.7% of those with possible HAM/TSP (P = 0.05). Upon study conclusion, the cumulative frequency of patients requiring CIC increased in both groups, from 2 to 6 in possible HAM/TSP and from 28 to 44 in definite HAM/TSP patients. The estimated time to need for CIC was 6.7 years (95%CI 6.5–7.0) in the possible HAM/TSP group compared to 5.5 years (95%CI 4.8–6.1) in the definite HAM/TSP group. Although both groups showed similarities in bladder dysfunction and tended to progress to requiring CIC over time, patients with possible HAM/TSP presented less severe manifestations at baseline and progressed more slowly than those with definite HAM/TSP.

• Adult
• Cohort Studies
• Disease Progression
• Female
• HTLV-I Infections/complications
• Human T-lymphotropic virus 1
• Humans
• Intermittent Urethral Catheterization/statistics & numerical data
• Male
• Middle Aged
• Paraparesis, Tropical Spastic/complications
• Prospective Studies
• Urinary Bladder Diseases/complications
• Urodynamics

• Conselho Nacional de Pesquisa (CNPq)
• Fundação Maria Emilia Pedreira de Carvalho

• Anxiety
• Depression
• HAM/TSP
• HTLV-1
• HTLV-1 infection
• Neglected tropical disease

• HTLV1
• infectious diseases
• myelopathy

• Human T-cell leukemia virus type 1
• Human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis
• Mirabegron
• Neurogenic bladder
• Urinary symptom score

• Central Nervous System Viral Diseases
• Child
• Enterovirus Infections
• Humans
• Myelitis/diagnosis
• Myelitis/epidemiology
• Myelitis/therapy
• Spinal Cord
• Spine

• HTLV-I infections
• HTLV-I-associated myelopathy
• Muscle spasticity
• Tropical spastic paraparesis

• Biomarker
• CXCL10
• Cerebrospinal fluid
• HTLV-1-associated myelopathy/tropical spastic paraparesis
• Human T-cell leukemia virus type I
• Neopterin

Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is an inflammatory disease of the spinal cord and clinically characterized by progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. The interaction between the host immune response and HTLV-1-infected cells regulates the development of HAM/TSP. HTLV-1 preferentially infects CD4⁺ T cells and is maintained by proliferation of the infected T cells. HTLV-1-infected cells rarely express viral antigens in vivo; however, they easily express the antigens after short-term culture. Therefore, such virus-expressing cells may lead to activation and expansion of antigen-specific T cell responses. Infected T cells with HTLV-1 and HTLV-1-specific CD8⁺ cytotoxic T lymphocytes invade the central nervous system and produce various proinflammatory cytokines and chemokines, leading to neuronal damage and degeneration. Therefore, cellular immune responses to HTLV-1 have been considered to play important roles in disease development of HAM/TSP. Recent studies have clarified the viral strategy for persistence in the host through genetic and epigenetic changes by HTLV-1 and host immune responses including T cell function and differentiation. Newly developed animal models could provide the opportunity to uncover the precise pathogenesis and development of clinically effective treatment. Several molecular target drugs are undergoing clinical trials with promising efficacy. In this review, we summarize recent advances in the immunopathogenesis of HAM/TSP and discuss the perspectives of the research on this disease.

• HAM/TSP
• HTLV-1
• Immunology
• Neurological disorders
• Pathogenesis

• Animals
• CD4-Positive T-Lymphocytes/drug effects
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/virology
• Cell Proliferation/drug effects
• Cytokines/biosynthesis
• Cytokines/immunology
• Disease Models, Animal
• Host-Pathogen Interactions/immunology
• Human T-lymphotropic virus 1/drug effects
• Human T-lymphotropic virus 1/immunology
• Human T-lymphotropic virus 1/pathogenicity
• Humans
• Immunity, Cellular/drug effects
• Immunologic Factors/therapeutic use
• Leukemia-Lymphoma, Adult T-Cell/drug therapy
• Leukemia-Lymphoma, Adult T-Cell/immunology
• Leukemia-Lymphoma, Adult T-Cell/pathology
• Leukemia-Lymphoma, Adult T-Cell/virology
• Lymphocyte Activation/drug effects
• Neurons/drug effects
• Neurons/immunology
• Neurons/pathology
• Neurons/virology
• Neuroprotective Agents/therapeutic use
• Paraparesis, Tropical Spastic/drug therapy
• Paraparesis, Tropical Spastic/immunology
• Paraparesis, Tropical Spastic/pathology
• Paraparesis, Tropical Spastic/virology
• Spinal Cord/drug effects
• Spinal Cord/immunology
• Spinal Cord/virology
• T-Lymphocytes, Cytotoxic/drug effects
• T-Lymphocytes, Cytotoxic/immunology
• T-Lymphocytes, Cytotoxic/virology
• Urinary Incontinence/drug therapy
• Urinary Incontinence/immunology
• Urinary Incontinence/pathology
• Urinary Incontinence/virology

Background: Vertical transmission of HTLV-1 could lead to the early development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This significantly affects quality of life and increases morbimortality. Objective: To describe the epidemiological and clinical characteristics of patients with early-onset HAM/TSP, defined as disease onset before 20 years of age. Methods: This is a retrospective study from an HTLV-1 clinical cohort between 1989 and 2019. We searched for medical records of patients with (1) diagnosis of HTLV-1 infection using two ELISA and/or one Western blot, (2) clinical diagnosis of HAM/TSP by neurological assessment, and (3) HAM/TSP symptom-onset before 20 years of age. Results: A total of 38 cases were identified in the cohort; 25 were female (66%). The median age of onset was 14 years old. 31 (82%) cases had HTLV-1 testing done among family members; 22 out of 25 tested mothers (88%) were HTLV-1 positive. Most patients (27/34) were breastfed for more than one year. Disease progression measured through EDSS and IPEC-1 showed an upward trend towards worsening spasticity with 18 patients (47%) eventually requiring mobility aids. Conclusions: Cases of early-onset HAM/TSP are not of rare occurrence, which translates into many more years of dependency, the use of mobility aids, and increased overall morbidity.

• HAM/TSP
• chronic infection
• inflammation
• myelopathy
• paraparesis

A high proviral load (PVL) is recognized as a risk factor for human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), but there is a lack of prospective studies evaluating whether or not HTLV-1 carriers with high PVL are at risk of developing HAM/TSP or other HTLV-1-related diseases. Here, we compare the incidence of clinical manifestations and the cytokine levels in 30 HTLV-1 carriers with high (> 50,000 copies/10⁶ PBMC) and an equal number of subjects with low proviral load. Participants were followed for 3 to 16 years (median of 11 years). The PVL, IFN-γ, TNF, and IL-10 levels were quantified at entry and at the end of the follow-up. Among the self-reported symptoms in the initial evaluation, only the presence of paresthesia on the hands was more frequent in the group with high PVL (p < 0.04). The production of IFN-γ was higher in the group with high PVL group (median of 1308 versus 686 pg/ml, p < 0.011) when compared with the control group in the first assessment. There was no difference in the occurrence of urinary symptoms or erectile dysfunction, periodontal disease, Sicca syndrome, and neurologic signs between the two groups during the follow-up. The observation that none of the HTLV-1 carriers with high PVL and with exaggerated inflammatory response progressed to HAM/TSP indicates that other factors in addition to the PVL and an exaggerated immune response are involved in the pathogenesis of HAM/TSP.

• HTLV-1
• HTLV-1 carriers
• HTLV-1-associated myelopathy
• Myelopathy
• Proviral load

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for Adult T-Cell Leukemia/Lymphoma (ATLL) and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HTLV-1 infects CD4⁺ T-cells via cell-to-cell transmission requiring reorganization of the cytoskeleton and expression of the viral transactivator and oncoprotein Tax. Viruses spread at the virological synapse (VS), a virus-induced specialized cell-cell contact, by polarized budding into synaptic clefts, and by cell surface transfer of viral biofilms (VBs). Since little is known about Tax’s role in formation of the VB, we asked which component of the VB is regulated by Tax and important for HTLV-1 transmission. Collagens are not only structural proteins of the extracellular matrix and basal membrane but also represent an important component of the VB. Here, we report that among the collagens known to be present in VBs, COL4 is specifically upregulated in the presence of HTLV-1 infection. Further, we found that transient expression of Tax is sufficient to induce COL4A1 and COL4A2 transcripts in Jurkat and CCRF-CEM T-cells, while robust induction of COL4 protein requires continuous Tax expression as shown in Tax-transformed T-cell lines. Repression of Tax led to a significant reduction of COL4A1/A2 transcripts and COL4 protein. Mechanistically, luciferase-based promoter studies indicate that Tax activates the COL4A2 and, to a less extent, the COL4A1 promoter. Imaging showing partial co-localization of COL4 with the viral Gag protein in VBs at the VS and transfer of COL4 and Gag to target cells suggests a role of COL4 in VB formation. Strikingly, in chronically infected C91-PL cells, knockout of COL4A2 impaired Gag transfer between infected T-cells and acceptor T-cells, while release of virus-like particles was unaffected. Taken together, we identified COL4 (COL4A1, COL4A2) as a component of the VB and a novel cellular target of Tax with COL4A2 appearing to impact virus transmission. Thus, this study is the first to provide a link between Tax’s activity and VB formation by hijacking COL4 protein functions.

• COL4A1
• COL4A2
• HTLV-1
• Tax-1
• collagen 4
• collagen IV
• viral biofilm
• virus transmission

As human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neurological disease, large scale studies to collect continuous clinical data have been difficult to conduct. Therefore, the incidence of comorbidities and drug utilization data remain unknown. When conducting trials to develop new drugs in rare disease such as HAM/TSP, historical control data obtained from registry studies would be useful, as cohorts in rare disease tend to be small. Long-term follow-up of patients with a chronic disease can also be challenging. In this study, we addressed the following two goals using registry data on patients (n = 486) enrolled in the Japanese HAM/TSP patient registry “HAM-net” from 2012 to 2016: 1) to clarify the epidemiological information of HAM/TSP such as the incidence of comorbidities and drug utilization and 2) to provide the real-world data on changes in lower limb motor dysfunction.

In HAM-net-registered patients, common comorbidities were fractures, herpes zoster, and uveitis, with incidences of 55.5, 10.4, and 6.5, respectively, per 1000 person-years. Every year, oral steroid treatment was administered in 48.2–50.7% of the HAM-net-registered patients and interferon-α treatment was used in 2.6–3.5% of patients. The median dose of oral prednisolone was low at 5.0 mg/day. The incidence of fractures and herpes zoster tended to be higher in the steroid-treated group than in the untreated group (fractures: 61.0 vs. 48.3, herpes zoster: 12.7 vs. 8.8, per 1000 person-years). The analysis of chronological change in Osame motor disability score (OMDS) indicated that the mean change in OMDS was + 0.20 [95% confidence intervals (CI): 0.14–0.25] per year in the one-year observation group (n = 346) and + 0.57 (95% CI: 0.42–0.73) over four years in the four-year observation group (n = 148). Significant deterioration of OMDS was noted in all subgroups with varying steroid use status.

This study revealed the incidence of comorbidities and drug utilization data in patients with HAM/TSP using registry data. Furthermore, this study provided real-world data on chronological changes in lower limb motor dysfunction in patients with HAM/TSP, indicating the utility of these data as historical controls.

• HAM/TSP
• HTLV-1
• Historical control
• Real-world data

• CXCL10
• HAM/TSP
• HTLV-1
• biomarker
• cerebrospinal fluid
• neopterin

More than 10 million people worldwide are infected with the retrovirus human T-cell lymphotropic virus type 1 (HTLV-1). Infection phenotypes can range from asymptomatic to severe adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy. HTLV-1, like human immunodeficiency virus type 1 (HIV-1), is a blood-borne pathogen and viral infection happens in a similar fashion, with the major mode of transmission through breastfeeding. There is a strong correlation between time of infection and disease development, with a higher incidence of ATLL in patients infected during childhood. There is no successful therapeutic or preventative regimen for HTLV-1. It is therefore essential to develop therapies to inhibit transmission or block the onset/development of HTLV-1 associated diseases. Recently, we have seen the overwhelming success of integrase strand transfer inhibitors (INSTIs) in the treatment of HIV-1. Previously, raltegravir was shown to inhibit HTLV-1 infection. Here, we tested FDA-approved and two Phase II HIV-1 INSTIs in vitro and in a cell-to-cell infection model and show that they are highly active in blocking HTLV-1 infection, with bictegravir (EC₅₀ = 0.30 ± 0.17 nM) performing best overall. INSTIs, in particular bictegravir, are more potent in blocking HTLV-1 transmission than tenofovir disproxil fumarate (TDF), an RT inhibitor. Our data suggest that HIV-1 INSTIs could present a good clinical strategy in HTLV-1 management and justifies the inclusion of INSTIs in clinical trials.

• HTLV-1
• INSTI
• PVL
• bictegravir
• elvitegravir
• integrase
• raltegravir

• Cognitive assessment
• HTLV-1
• Inflammation
• Tropical spastic paraparesis

Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of both adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is clinically characterized by chronic progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. Given its well-characterized clinical presentation and pathophysiology, which is similar to the progressive forms of multiple sclerosis (MS), HAM/TSP is an ideal system to better understand other neuroimmunological disorders such as MS. Since the discovery of HAM/TSP, large numbers of clinical, virological, molecular, and immunological studies have been published. The host-virus interaction and host immune response play an important role for the development with HAM/TSP. HTLV-1-infected circulating T-cells invade the central nervous system (CNS) and cause an immunopathogenic response against virus and possibly components of the CNS. Neural damage and subsequent degeneration can cause severe disability in patients with HAM/TSP. Little progress has been made in the discovery of objective biomarkers for grading stages and predicting progression of disease and the development of molecular targeted therapy based on the underlying pathological mechanisms. We review the recent understanding of immunopathological mechanism of HAM/TSP and discuss the unmet need for research on this disease.

• HTLV-1-associated myelopathy/tropical spastic paraparesis
• human T-lymphotropic virus type 1
• immunology
• neurological disorders
• pathogenesis

In this study we characterized the TCR repertoire profiles in patients with chronic progressive inflammatory neurological disorders including HAM/TSP, associated with human T-cell lymphotropic virus type I (HTLV-I) infection, and multiple sclerosis (MS), an inflammatory, demyelinating disease of the CNS of unknown etiology. We hypothesized that a T-cell receptor (TCR) clonal repertoire ‘signature’ could distinguish HAM/TSP patients from healthy controls, as well as from patients with a more heterogeneous CNS-reactive inflammatory disease such as MS. In this study, we applied an unbiased molecular technique – unique molecular identifier (UMI) library-based strategy to investigate with high accuracy the TCR clonal repertoire by high throughput sequencing (HTS) technology. cDNA-TCR β-chain libraries were sequenced from 2 million peripheral mononuclear cells (PBMCs) in 14 HAM/TSP patients, 34 MS patients and 20 healthy controls (HC). While HAM/TSP patients showed a higher clonal T-cell expansion compared to MS and HC, increase of the TCR clonal expansion was inversely correlated with the diversity of TCR repertoire in all subjects. In addition, longitudinal analysis of TCR repertoires from HAM/TSP patients demonstrated a correlation of the TCR clonal expansion with HTLV-I proviral load. Surprisingly, MS patients showed a higher diversity of TCR repertoires than other groups. Despite higher TCR clonal expansions in HAM/TSP patients, no disease-specific TCRs were shared among patients. Only non-shared or “private” TCR repertoires was observed. While no clones that shared the same CDR3 amino acid sequences were seen in either HC or MS patients, there was a cluster of related CDR3 amino acid sequences observed for 18 out of 34 MS patients when evaluated by phylogenetic tree analysis. This suggests that a TCR-repertoire signature may be identified in a subset of patients with MS.

• Cohort Studies
• Electric Stimulation/methods
• Electromyography/methods
• Female
• Humans
• Male
• Mastoid
• Middle Aged
• Muscle, Skeletal/physiopathology
• Observer Variation
• Paraparesis, Tropical Spastic/diagnosis
• Paraparesis, Tropical Spastic/physiopathology
• Reproducibility of Results
• Vestibular Evoked Myogenic Potentials

• Pró-Reitoria de Pesquisa, Universidade Federal de Minas Gerais
• Fundação de Amparo à Pesquisa do Estado de Minas Gerais (BR)
• Conselho Nacional de Desenvolvimento Científico e Tecnológico
• Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

• Cell-mediated immune response
• Chimeric peptide vaccine
• HTLV-1
• ISCOMATRIX
• MPLA
• Mucosal immunity

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. While the disease usually progresses slowly without remission, there is a subgroup of patients with rapid progression and another subgroup with very slow progression. However, there have been no reports to date that have successfully determined the criteria to differentiate these subgroups. Therefore, we initially conducted a statistical modeling analysis to explore representative patterns of disease progression using data from our nationwide HAM/TSP patient registration system (“HAM-net”). The latent class mixed model analysis on the retrospective data (n = 205) of disease progression measured by the change in Osame Motor Disability Score from the onset of the disease to diagnosis demonstrated three representative progression patterns of HAM/TSP. Next, to test the effect of the progression rate at the initial phase of the disease on long-term prognosis, we divided 312 “HAM-net” registered patients into three groups (rapid, slow, and very slow progressors) based on the progression rate, then analyzed long-term functional prognosis of each group using the Kaplan–Meier method. Our data clearly demonstrated that the rapid progression at the early phase of the disease is an important poor prognostic factor. Moreover, to determine the biomarkers capable of discriminating the difference in disease activity, we compared the value of potential biomarkers of HAM/TSP among rapid (n = 15), slow (n = 74), very slow (n = 7), and controls (non-HAM/TSP patients, n = 18). The cerebrospinal fluid (CSF) levels of neopterin and C-X-C motif chemokine 10 (CXCL10) were the most valuable markers to discriminate among rapid, slow, and very slow progressors. To differentiate between rapid and slow progressors, the cut-off values of neopterin and CXCL10 were determined to be 44 pmol/mL and 4400 pg/mL, respectively. Furthermore, to differentiate between slow and very slow progressors, these values were determined to be 5.5 pmol/mL and 320 pg/mL, respectively. Notably, we found that CSF levels of these markers in very slow progressors were within the reference range. Thus, we propose a new classification criteria for disease activity of HAM/TSP that may contribute to improving the treatment algorithm for HAM/TSP.

• CXCL10
• HAM/TSP
• HTLV-1
• biomarker
• classification criteria
• disease activity
• neopterin

• Adult
• Aged
• Female
• HTLV-I Antibodies/blood
• HTLV-I Infections/epidemiology
• HTLV-I Infections/virology
• Human T-lymphotropic virus 1/immunology
• Human T-lymphotropic virus 1/isolation & purification
• Humans
• Incidence
• Male
• Martinique/epidemiology
• Middle Aged
• Paraparesis, Tropical Spastic/epidemiology
• Paraparesis, Tropical Spastic/immunology
• Paraparesis, Tropical Spastic/virology
• Poisson Distribution
• Public Health
• Risk Factors
• Seroepidemiologic Studies
• Spinal Cord Diseases/epidemiology
• Spinal Cord Diseases/immunology
• Spinal Cord Diseases/virology
• Time Factors

Five to ten million individuals are infected by Human T-cell Leukemia Virus type 1 (HTLV-1). HTLV-1 is transmitted through prolonged breast-feeding, by sexual contacts and by transmission of infected T lymphocytes through blood transfusion. One to ten percent of infected carriers will develop a severe HTLV-1-associated disease: Adult-T-cell leukemia/lymphoma (ATLL), or a neurological disorder named Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM). In vivo, HTLV-1 is mostly detected in CD4⁺ T-cells, and to a lesser extent in CD8⁺ T cells and dendritic cells. There is a strong correlation between HTLV-1 proviral load (PVL) and clinical status of infected individuals. Thus, reducing PVL could be part of a strategy to prevent or treat HTLV-1-associated diseases among carriers. Treatment of ATLL patients using conventional chemotherapy has very limited benefit. Some chronic and acute ATLL patients are, however, efficiently treated with a combination of interferon α and zidovudine (IFN-α/AZT), to which arsenic trioxide is added in some cases. On the other hand, no efficient treatment for TSP/HAM patients has been described yet. It is therefore crucial to develop therapies that could either prevent the occurrence of HTLV-1-associated diseases or at least block the evolution of the disease in the early stages. In vivo, reverse transcriptase (RT) activity is low in infected cells, which is correlated with a clonal mode of viral replication. This renders infected cells resistant to nucleoside RT inhibitors such as AZT. However, histone deacetylase inhibitors (HDACi) associated to AZT efficiently induces viral expression and prevent de novo cellular infection. In asymptomatic STLV-1 infected non-human primates, HDACi/AZT combination allows a strong decrease in the PVL. Unfortunately, rebound in the PVL occurs when the treatment is stopped, highlighting the need for better antiviral compounds. Here, we review previously used strategies targeting HTLV-1 replication. We also tested a series of HIV-1 RT inhibitors in an in vitro anti-HTLV-1 screen, and report that bis-POM-PMEA (adefovir dipivoxil) and bis-POC-PMPA (tenofovir disoproxil) are much more efficient compared to AZT to decrease HTLV-1 cell-to-cell transmission in vitro. Our results suggest that revisiting already established antiviral drugs is an interesting approach to discover new anti-HTLV-1 drugs.

• AZT
• HTLV-1
• acyclic nucleoside phosphonates and thiophosphonates
• antiviral therapy
• cell–cell transmission
• prodrugs
• proviral load

• Adult
• Aged
• Antibodies, Monoclonal, Humanized/administration & dosage
• Antibodies, Monoclonal, Humanized/adverse effects
• Antibodies, Monoclonal, Humanized/pharmacokinetics
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/pharmacokinetics
• Area Under Curve
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Exanthema/chemically induced
• Female
• Human T-lymphotropic virus 1/isolation & purification
• Humans
• Male
• Middle Aged
• Paraparesis, Tropical Spastic/drug therapy
• Paraparesis, Tropical Spastic/immunology
• Receptors, CCR4/antagonists & inhibitors
• T-Lymphocytes/immunology
• Viral Load

• Animals
• CD4-Positive T-Lymphocytes/metabolism
• CD4-Positive T-Lymphocytes/virology
• Cyclic AMP Response Element-Binding Protein/genetics
• Cyclic AMP Response Element-Binding Protein/metabolism
• Female
• Gene Products, tax/genetics
• Gene Products, tax/metabolism
• Group IV Phospholipases A2/genetics
• Group IV Phospholipases A2/metabolism
• HTLV-I Infections/drug therapy
• HTLV-I Infections/metabolism
• HTLV-I Infections/virology
• Host-Pathogen Interactions
• Human T-lymphotropic virus 1/pathogenicity
• Humans
• Indoles/pharmacology
• Infant, Newborn
• Jurkat Cells
• Leukotriene B4/metabolism
• Lipoxygenase Inhibitors/pharmacology
• Male
• Mice, Mutant Strains
• NF-kappa B/genetics
• NF-kappa B/metabolism