HTLV-1-associated Myelopathy/tropical Spastic Paraparesis Research Articles

What is the role of the thioredoxin antioxidant complex in relation to HAM/TSP?

We have little information about the definite role of the thioredoxin antioxidant complex system during viral infection, particularly during human T-cell lymphotropic virus type 1 (HTLV-1) infection and the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) state. Therefore, we conducted comprehensive next-generation sequencing (NGS) analysis to determine Trx system expression changes in three categories of subjects: sero-negative HTLV-1 individuals, asymptomatic HTLV-1 people and HAM/TSP patients. We found that Trx capacity is reduced in the HAM/TSP state compared to healthy individuals, which indicates increasing inflammation and reduction of apoptosis, which might contribute to the progression of inflammation in the spinal cord, which in turn may develop into the HAM/TSP state.

Impact of fractures and orthopedic surgeries in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis.

INTRODUCTION In patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) gait disturbance is a predominant feature that leads to falls and fractures, which can further aggravate disability. We sought to evaluate the impact of fractures and orthopedic surgeries in patients with HAM/TSP. METHODS: We retrieved the medical records of HAM/TSP patients enrolled in our study center’s HTLV-1 clinical cohort between 1989-2018. The selection criteria included: (1) diagnosis of HTLV-1 infection using two enzyme-linked immunosorbent assays and/or a confirmatory test, (2) clinical diagnosis of HAM/TSP by neurological assessment, and (3) fractures associated with HAM/TSP. RESULTS: We identified 24 cases of fractures, 70% of which were females. The median age at the time of fracture was 60 years (IQR=24). Six cases reported fractures in patients under 45 years old. Ten patients (42%) had hip/coccyx fractures, seven (29%) were in the lower extremities, and four (17%) in the upper extremities. Half of these patients reported the use of wheelchairs. Five patients who had previously used canes required the use of wheelchairs after the reported fracture. Eight patients underwent corrective orthopedic surgery as a result of the fracture. CONCLUSIONS: For HAM/TSP patients, fractures are a complication that can exacerbate their severe impairment.

Therapeutic responses to interferon-alpha in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP): Differing clinical responses to leukocyte-derived human interferon-alpha versus recombinant interferon-alpha

Introduction: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive spinal cord syndrome seen in patients infected by human T-lymphotropic virus type 1 (HTLV-1). Initial infection by the virus is usually asymptomatic. As the disease progresses, a se

Complete genome sequence of human T-cell lymphotropic type 1 from patients with different clinical profiles, including infective dermatitis

The HTLV-1 is the first human retrovirus and is associated with several clinical syndromes, however, the pathogenesis of these clinical manifestations is still not fully understood. Furthermore, there are few complete genomes publicly available, about 0.12 complete genomes per 10,000 infected individuals and the databases have a major deficiency of sequences information. This study generated and characterized 31 HTLV-1 complete genomes sequences derived from individuals with Tropical Spastic Paraparesis/HTLV-1-Associated Myelopathy (TSP/HAM), Adult T-cell leukemia/lymphoma (ATL), infective dermatitis associated to HTLV-1 (IDH) and asymptomatic patients. These sequences are associated to clinical and epidemiological information about the patients. The sequencing data generated on Ion Torrent PGM platform were assembled and mapped against the reference HTLV-1 genome. These sequences were genotyped as Cosmopolitan subtype, Transcontinental subgroup. We identified the variants in the coding regions of the genome of the different clinical profiles, however, no statistical relation was detected. This study contributed to increase of HTLV-1 complete genomes in the world. Furthermore, to better investigate the contribution of HTLV-1 mutations for the disease outcome it is necessary to evaluate the interaction of the viral genome and characteristics of the human host.

TREX1 531C>T Polymorphism is Associated with High Proviral Load Levels in HTLV-1-Infected Persons.

Human T-lymphotropic virus type 1 (HTLV-1) deregulates the immune system and cell cycle, resulting in loss of immune tolerance and disease, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Three prime repair exonuclease 1 (TREX1) maintains innate immune tolerance of the host and host-cell permissiveness to retroviral infections. TREX1 polymorphisms may influence the course of infection and autoimmune manifestations. The influence of TREX1 531C/T polymorphism was investigated in HTLV-1 infection and development of symptoms among 151 persons infected with HTLV-1 (32 HAM/TSP, 19 rheumatologic manifestations, two dermatitis, five more than one diagnosis, two probable HAM/TSP, and 91 asymptomatic individuals) and 100 uninfected persons in the control group. Polymorphism genotyping and proviral load quantification were performed by real-time polymerase chain reaction (PCR) and antinuclear antibodies (ANAs) were screened by an indirect immunofluorescence assay. No statistically significant difference was found in polymorphism genotype and allele frequencies between the infected and control groups. HAM/TSP patients showed higher frequency of TT genotype than asymptomatic persons (p = 0.0339). Proviral load was significantly higher among individuals with CT/TT genotypes and CC genotype carriers had lower proviral load and higher levels of proinflammatory cytokines. ANAs were present only in the HAM/TSP group. TREX1 531C>T polymorphism seems to be associated with TREX-1 regulation and HTLV-1 infection.

HTLV-1 proviral load in infective dermatitis associated with HTLV-1 does not increase after the development of HTLV-1-associated myelopathy/tropical spastic paraparesis and does not decrease after IDH remission.

IntroductionInfective dermatitis associated with HTLV-1 (IDH) is a recurrent eczema which affects children vertically infected with HTLV-1. In Bahia, Brazil, we recently reported that 47% of IDH patients also develop juvenile HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive disabling disorder which is typically reported in adult HTLV-1 carriers. IDH may also predispose to adult T-cell leukemia/lymphoma, a neoplasm associated with HTLV-1. The factors relating to the development of HTLV-1-associated juvenile diseases have not yet been defined. HTLV-1 proviral load (PVL) is one of the main parameters related to the development of HTLV-1 associated diseases in adults. In the current study, we investigated the role of PVL in IDH and juvenile HAM/TSP.Methodology/Principal findingsThis is a cohort study that included fifty-nine HTLV-1 infected children and adolescents, comprising 16 asymptomatic carriers, 18 IDH patients, 20 patients with IDH and HAM/TSP (IDH/HAM/TSP) and five with HAM/TSP. These patients were followed-up for up to 14 years (median of 8 years). We found that PVL in IDH and IDH/HAM/TSP patients were similarly higher than PVL in juvenile asymptomatic carriers (p<0.0001). In those IDH patients who developed HAM/TSP during follow-up, PVL levels did not vary significantly. HAM/TSP development did not occur in those IDH patients who presented high levels of PVL. IDH remission was associated with an increase of PVL. Inter-individual differences in PVL were observed within all groups. However, intra-individual PVL did not fluctuate significantly during follow-up.Conclusions/SignificanceHigh PVL in IDH patients was not necessary indicative of progression to HAM/TSP. PVL did not decrease after IDH remission. The maintenance of high PVL after remission could favor early development of ATL. Therefore, IDH patients would have to be followed-up even after remission of IDH and for a long period of time.

HTLV-1 Associated Neurological Complex. What is Hidden below the Water?

The human T-cell lymphotropic virus type 1 (HTLV-1) infects 5-10 million people worldwide and causes fatal and disabling diseases in a significant proportion of them. A chronic myelitis named HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the typical neurological manifestation of HTLV-1. However, other neurological syndromes can be either associated with HAM/TSP or occur in isolation in the HTLV-1 infected individual. Although this fact has been widely described over the years, it has been somewhat neglected by the mainstream literature, which has been largely focused on HAM/TSP. Cognitive dysfunction, encephalopathy, neurogenic bladder, motor neuron disease, inflammatory myopathies, polyneuropathy, and dysautonomia can also occur in the HTLV-1 infected patient and may remain unnoticed to the unsuspecting physician. In the present review, we intend to draw attention, primarily to the infectious disease specialist and to the general practitioner, to the fact that HTLV-1 has a broader neurological spectrum than the designation HAM/TSP suggests and that infected individuals may harbor other neurological syndromes in addition to HAM/TSP.

An insight to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) pathogenesis; evidence from high-throughput data integration and meta-analysis

BackgroundHuman T-lymphotropic virus 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive disease of the central nervous system that significantly affected spinal cord, nevertheless, the pathogenesis pathway and reliable biomarkers have not been well determined. This study aimed to employ high throughput meta-analysis to find major genes that are possibly involved in the pathogenesis of HAM/TSP.ResultsHigh-throughput statistical analyses identified 832, 49, and 22 differentially expressed genes for normal vs. ACs, normal vs. HAM/TSP, and ACs vs. HAM/TSP groups, respectively. The protein–protein interactions between DEGs were identified in STRING and further network analyses highlighted 24 and 6 hub genes for normal vs. HAM/TSP and ACs vs. HAM/TSP groups, respectively. Moreover, four biologically meaningful modules including 251 genes were identified for normal vs. ACs. Biological network analyses indicated the involvement of hub genes in many vital pathways like JAK-STAT signaling pathway, interferon, Interleukins, and immune pathways in the normal vs. HAM/TSP group and Metabolism of RNA, Viral mRNA Translation, Human T cell leukemia virus 1 infection, and Cell cycle in the normal vs. ACs group. Moreover, three major genes including STAT1, TAP1, and PSMB8 were identified by network analysis. Real-time PCR revealed the meaningful down-regulation of STAT1 in HAM/TSP samples than AC and normal samples (P = 0.01 and P = 0.02, respectively), up-regulation of PSMB8 in HAM/TSP samples than AC and normal samples (P = 0.04 and P = 0.01, respectively), and down-regulation of TAP1 in HAM/TSP samples than those in AC and normal samples (P = 0.008 and P = 0.02, respectively). No significant difference was found among three groups in terms of the percentage of T helper and cytotoxic T lymphocytes (P = 0.55 and P = 0.12).ConclusionsHigh-throughput data integration disclosed novel hub genes involved in important pathways in virus infection and immune systems. The comprehensive studies are needed to improve our knowledge about the pathogenesis pathways and also biomarkers of complex diseases.

EOS, an Ikaros family zinc finger transcription factor, interacts with the HTLV-1 oncoprotein Tax and is downregulated in peripheral blood mononuclear cells of HTLV-1-infected individuals, irrespective of clinical statuses

BackgroundEOS plays an important role in maintaining the suppressive function of regulatory T cells (Tregs), and induces a regulated transformation of Tregs into T helper-like cells, which are capable of secreting proinflammatory cytokines in response to specific inflammatory signals. Meanwhile, significant reduction in Treg activity along with production of proinflammatory cytokines has been reported in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).MethodsIn this study, to examine whether there is an alteration in EOS expression in peripheral blood mononuclear cells (PBMCs) derived from HTLV-1-infected individuals especially HAM/TSP, we investigated the expression of HTLV-1 tax genotype, proviral load (PVL), and the mRNA expression of tax, HBZ and EOS in HTLV-1 infected individuals including adult T-cell leukemia/lymphoma (ATL), HAM/TSP, or asymptomatic carriers. The expression levels of EOS mRNA and protein in various HTLV-1-infected or uninfected human T-cell lines were also investigated.ResultsEOS was highly expressed at the protein level in most HTLV-1 infected T-cell lines, and was augmented after the HTLV-1 regulatory factor Tax was induced in a Tax-inducible JPX-9 cell line. Immunoprecipitation experiments demonstrated a physical interaction between EOS and the viral regulatory protein Tax, but not HBZ. Meanwhile, there was a significant decrease in EOS mRNA levels in PBMCs of HTLV-1 infected individuals irrespective of their clinical statuses. We found an inverse correlation between EOS mRNA levels and HTLV-1 PVL in ATL patients, and positive correlations between both EOS mRNA load and PVL, and EOS and HBZ mRNA load in HAM/TSP patients, whereas this correlation was not observed in other clinical statuses.ConclusionsThese findings suggest that both Tax and HBZ can alter the expression of EOS through undetermined mechanisms, and dysregulated expression of EOS in PBMCs of HTLV-1 infected individuals may contribute to the pathological progression of HTLV-1-associated diseases, such as ATL and HAM/TSP.

HTLV-1 CTCF-binding site is dispensable for in vitro immortalization and persistent infection in vivo

BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The exact mechanism(s) through which latency and disease progression are regulated are not fully understood. CCCTC-binding factor (CTCF) is an 11-zinc finger, sequence-specific, DNA-binding protein with thousands of binding sites throughout mammalian genomes. CTCF has been shown to play a role in organization of higher-order chromatin structure, gene expression, genomic imprinting, and serve as a barrier to epigenetic modification. A viral CTCF-binding site (vCTCF-BS) was previously identified within the overlapping p12 (sense) and Hbz (antisense) genes of the HTLV-1 genome. Thus, upon integration, HTLV-1 randomly inserts a vCTCF-BS into the host genome. vCTCF-BS studies to date have focused primarily on HTLV-1 chronically infected or tumor-derived cell lines. In these studies, HTLV-1 was shown to alter the structure and transcription of the surrounding host chromatin through the newly inserted vCTCF-BS. However, the effects of CTCF binding in the early stages of HTLV-1 infection remains unexplored. This study examines the effects of the vCTCF-BS on HTLV-1-induced in vitro immortalization and in vivo viral persistence in infected rabbits.ResultsHTLV-1 and HTLV-1∆CTCF LTR-transactivation, viral particle production, and immortalization capacity were comparable in vitro. The total lymphocyte count, proviral load, and Hbz gene expression were not significantly different between HTLV-1 and HTLV-1∆CTCF-infected rabbits throughout a 12 week study. However, HTLV-1∆CTCF-infected rabbits displayed a significantly decreased HTLV-1-specific antibody response compared to HTLV-1-infected rabbits.ConclusionsMutation of the HTLV-1 vCTCF-BS does not significantly alter T-lymphocyte transformation capacity or early in vivo virus persistence, but results in a decreased HTLV-1-specific antibody response during early infection in rabbits. Ultimately, understanding epigenetic regulation of HTLV-1 gene expression and pathogenesis could provide meaningful insights into mechanisms of immune evasion and novel therapeutic targets.

Dermatologic Manifestations in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

Abstract- The human T cell lymphotropic virus type-1 (HTLV-1) is associated with adult T cell leukemia/lymphoma (ATL) and other disorders, including a slowly progressive demyelinating paraparesis, known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Dermatologic manifestations are common in patients infected with HTLV-1 infection. In this study, we evaluated the dermatologic lesions associated with HAM/TSP patients in Mashhad, Iran. Dermatological findings of 37 patients with HAM/TSP were investigated and compared with those of an HTLV-1 negative control group. A cutaneous biopsy was performed as needed, and the results were statistically analyzed. Results of the present study showed that 34 cases with HAM/TSP (91.9%) and 24 cases in the control group (64.9%) had at least one skin lesion or history of skin lesion before (P=0.010). Xerosis was found in 22 persons (59.5%) in the case group and 4 persons in the control group (10.8%) (P=0.000). Only xerosis was significantly associated with HAM/TSP. Skin manifestations were quite frequent in patients with HAM/TSP. Xerosis was significantly associated with HAM/TSP

Noninvasive Detection of Antibodies to Human T-Cell Lymphotropic Virus Types 1 and 2 by Use of Oral Fluid

Human T-lymphotropic viruses type 1 and 2 (HTLV-1/2) are prevalent in endemic clusters globally, and HTLV-1 infects at least 5 to 10 million individuals. Infection can lead to inflammation in the spinal cord, resulting in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), or adult T cell leukemia/lymphoma (ATL). Obtaining venous blood for serological screening, typically performed using enzyme immunoassays (EIAs), is invasive, sometimes socially unacceptable, and has restricted large-scale seroprevalence studies. Collecting oral fluid (OF) is a noninvasive alternative to venesection. In this study, an IgG antibody capture EIA was developed and validated to detect anti-HTLV-1/2 IgG in OF. OF and plasma specimens were obtained from seropositive HTLV-1/2-infected patients attending the National Centre for Human Retrovirology (n = 131) and from HTLV-1/2-uninfected individuals (n = 64). The assay showed good reproducibility and high diagnostic sensitivity (100%) and specificity (100%) using both OF and plasma. The Murex HTLV I+II commercial assay was evaluated and did not detect anti-HTLV-1/2 IgG in 14% (5/36) of OF specimens from seropositive donors. The reactivities of OF and plasma in the IgG capture correlated strongly (r = 0.9290) and were not significantly affected by delayed extraction when held between 3°C and 45°C for up to 7 days to simulate field testing. The use of OF serological screening for HTLV-1/2 infection could facilitate large-scale seroprevalence studies, enabling active surveillance of infection on a population level.

Abnormal vitamin D and lipid profile in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients.

The HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease of host-HTLV-1 interactions. In many virus-associated diseases and multiple sclerosis, the importance of vitamin-D and lipid profile has been demonstrated, thus similarly, their impacts were evaluated in HAM/TSP patients, in this study. Vitamin D and lipid profile were assessed in 120 healthy subjects (HSs), along with a proviral load (PVL) in 91 HAM/TSPs and 169 HTLV-1 carriers (ACs). The mean level of triglyceride and LDL in the HAM/TSPs were higher than HSs (P = 0.008 and 0.008, respectively), but no significant difference has been found between ACs and HSs. However, the level of HDL and vitamin-D in the HAM/TSP subjects were lower than HSs (P = 0.01 and P = 0.006, respectively). In HTLV-1 infected subjects, PVL was statistically associated with cholesterol (R = 0.24, P = 0.038), triglycerides (R = 0.26, P = 0.01) and HDL (R = 0.28, P = 0.001), and in HAM/TSPs there was a strong association between the severity of the disease, as determined by the OMDS and cholesterol (P = 0.01). Furthermore, in the HAM/TSPs, positive correlations between vitamin-D and age (R = 0.23, P = 0.028) and triglycerides (R = 0.38, P = 0.001) were found, also a significant correlation between PVL and LDL (R = 0.21, P = 0.001) and a weak correlation between PVL and OMDS (R = 0.4, P = 0.07) were noted. However, there was no correlation between PVL and urinary disturbance. Furthermore, PVL range of more than 600 copies/104 lymphocytes had a strong correlation with OMDS (P = 0.05), but not with urinary disturbance. It's more likely that HAM/TSP patients have an imbalanced lipid profile and low levels of vitamin D and may represent a potentially useful target for intervention in HTLV-1 associated diseases.

Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One.

Human T-lymphotropic virus 1 (HTLV-1) was the first recognized human retrovirus. Infection can lead to two main symptomatologies: adult T-cell lymphoma/leukemia (ATLL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Each manifestation is associated with distinct characteristics, as ATLL presents as a leukemia-like disease, while HAM/TSP presents as severe inflammation in the central nervous system, leading to paraparesis. Previous studies have identified molecules associated with disease development, e.g., the downregulation of Foxp3 in Treg cells was associated with increased risk of HAM/TSP. In addition, elevated levels of CXCL10, CXCL9, and Neopterin in cerebrospinal fluid also present increased risk. However, these molecules were only associated with specific patient groups or viral strains. Furthermore, the majority of studies did not jointly compare all clinical manifestations, and robust analysis entails the inclusion of both ATLL and HAM/TSP. The low numbers of samples also pose difficulties in conducting gene expression analysis to identify specific molecular relationships. To address these limitations and increase the power of manifestation-specific gene associations, meta-analysis was performed using publicly available gene expression data. The application of supervised learning techniques identified alterations in two genes observed to act in tandem as potential biomarkers: GBP2 was associated with HAM/TSP, and CD40LG with ATLL. Together, both molecules demonstrated high sample-classification accuracy (AUC values: 0.88 and 1.0, respectively). Next, other genes with expression correlated to these genes were identified, and we attempted to relate the enriched pathways identified with the characteristic of each clinical manifestation. The present findings contribute to knowledge surrounding viral progression and suggest a potentially powerful new tool for the molecular classification of HTLV-associated diseases.

Collagen IV (COL4A1, COL4A2), a Component of the Viral Biofilm, Is Induced by the HTLV-1 Oncoprotein Tax and Impacts Virus Transmission.

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.

Real-world clinical course of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Japan

BackgroundAs 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.ResultsIn 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.ConclusionsThis 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.

Cerebrospinal fluid CXCL10 as a surrogate marker of therapy-response and therapy-predict for HTLV-1-Associated myelopathy/tropical spastic paraparesis

Since HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a debilitating, progressive disease with no effective treatments, there is a dire need to develop a novel therapy that truly improves the long-term functional prognosis. However, this true endpoint is virtually impossible to consider as a primary endpoint in clinical trials, as it takes decades. Therefore, development of surrogate markers that enable to assess the effectiveness of new interventions more rapidly with greater accuracy is essential. Currently, there are several candidate surrogate markers for HAM/TSP. Cerebrospinal fluid (CSF) CXCL10 in particular is involved in the pathogenesis and correlates with disease progression. Changes in surrogate marker levels should be observed in response to treatment and they should correlate with prognosis. Here, we investigated these aspects of several markers, including CSF CXCL10. Patient information, motor function evaluation results, and CSF examination data from 13 patients with HAM/TSP who received steroid pulse therapy were collected retrospectively. We compared the levels of CXCL10 and neopterin, total protein, cell counts, anti-HTLV-1 antibody titer (all CSF markers), and Osame motor disability scores (OMDS) before and after pulse therapy. In conclusion, CXCL10 and neopterin levels in CSF declined in response to steroid pulse therapy and correlated with changes in prognosis based on continuation of treatment. In addition, patients with HAM/TSP who benefited from steroid pulse therapy had high CSF CXCL10 levels. Therefore, the CSF CXCL10 level would be useful as a surrogate marker of therapy-response and therapy-predict in patients with HAM/TSP.

Population-based prevalence of human T-lymphotropic virus type 1 in sub-Saharan Africa: a systematic review and meta-analysis.

Human T-cell lymphotropic virus type 1 (HTLV-1), the causative agent of adult T-cell leukaemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), is endemic in sub-Saharan Africa (SSA) and poses a high morbidity and mortality risk. Its prevalence in the general population is poorly understood. The potential for prevention motivated us to do a systematic review and meta-analysis of population-based studies to estimate the prevalence of HTLV-1 in SSA. A comprehensive, no-limit search was conducted in EMBASE, PubMed, Web of Science and the Cochrane Library from their inception dates to March 2019. Population-based studies presenting data on HTLV-1 in sub-Saharan Africa were included. Pooled prevalence was estimated using a random-effects meta-analysis. A total of 21 studies were included, representing 42297 participants. The pooled HTLV-1 seroprevalence was 3.19% (95% CI 2.36-4.12%) with variations across year of study. Prevalence of HTLV-1 positively correlated with year of study (β=0.0036, P=0.007). Participants from Central, Western and Southern Africa had a seroprevalence of 4.16% (95% CI 2.43-6.31%), 2.66% (95% CI 1.80-3.68%) and 1.56% (95% CI 0.48-3.15%), respectively. Our findings suggest that HTLV-1 infection is a public health concern in SSA and highlight the need to implement effective preventive programmes and interventions aimed at reducing the burden of this common yet neglected infection.

Cerebrospinal Fluid CXCL10 as a Candidate Surrogate Marker for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a debilitating, progressive disease without effective treatment; therefore, development of disease modifying therapy that improves long-term functional outcomes is an unmet need for patients. However, it is virtually impossible to consider this as a primary endpoint in clinical trials owing to the prolonged disease course. Therefore, development of surrogate markers that help predict the effectiveness of new interventions is essential. Currently, several candidate surrogate markers have been identified for HAM/TSP. Cerebrospinal fluid (CSF) C-X-C motif chemokine 10 (CXCL10) is involved in the pathogenesis of HAM/TSP and was shown to correlate with disease progression. However, it remains unclear whether changes in CSF CXCL10 levels are observed in response to treatment and whether these correlate with prognosis. Here we investigated several markers, including CSF CXCL10, in this respect. Data pertaining to patient characteristics and results of motor function evaluation and CSF examination of 13 HAM/TSP patients who received steroid treatment were retrospectively analyzed. Osame motor disability scores (OMDS), 10 m walking time, and CSF levels of CXCL10, neopterin, total protein, cell counts, and anti-HTLV-1 antibody titer were compared before and after steroid therapy. Levels of all CSF markers, with the exception of cell count, were significantly decreased after treatment. Nine of the 13 patients (69.2%) showed improvement in OMDS and were considered responders. Pre-treatment CSF levels of CXCL10 and anti-HTLV-1 antibody titer in responders were higher than those in non-responders (p = 0.020 and p = 0.045, respectively). Patients who continued low-dose oral prednisolone maintenance therapy after methylprednisolone pulse therapy showed sustained improvement in OMDS and CSF CXCL10 and neopterin levels lasting for 2 years. In contrast, OMDS and the CSF marker levels in patients who discontinued treatment returned to pre-treatment levels. This rebound phenomenon was also observed in patients who discontinued oral prednisolone therapy independently of pulse therapy. Our findings suggest that CSF CXCL10 may serve as a therapy-response and therapy-predictive marker for HAM/TSP. In addition, since decrease in CSF CXCL10 level was associated with good functional prognosis, CSF CXCL10 is a potential surrogate marker for treatment of HAM/TSP.

Balance Impairments in Patients with Human T-Cell Lymphotropic Virus Type 1 Infection

The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus from the Retroviridae family that infects cluster of differentiation 4 (CD4) T-lymphocytes and stimulates their proliferation. A severe consequence of this infection can be the HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is associated with a progressive demyelinating disease of the upper motor neurons. The HAM/TSP conditions frequently present with neurological complaints such as gait impairment, sphincter disturbances, and several sensory losses. We compared findings from the posturographic evaluation from the asymptomatic HTLV-1 infected subjects, HTLV-1 infected subjects having HAM/TSP, and control group database. A force plate was used to record the postural oscillations. Analysis of variance and multivariate linear discriminant analysis were used to compare the data obtained from the three groups of participants. In general, HAM/TSP patients had worse postural balance control than did the HTLV-1 patients and the controls (p < 0.05). We found that in six out of ten parameters of the postural balance control, there was a gradual increase in impairment from control to HTLV-1 to HAM/TSP groups. All parameters had higher values with the subject’s eyes closed. The multivariate linear discriminant analysis showed there was a reasonable difference in results between the control and HAM/TSP groups, and the HTLV-1 group was at the intersecting area between them. We found that HAM/TSP patients had worse balance control than did HTLV-1 infected patients and the control group, but asymptomatic HTLV-1 infected patients represent an intermediate balance control status between controls and HAM/TSP patients. Posturographic parameters can be relied on to identify subtle changes in the balance of HTLV-1 patients and to monitor their functional loss. HTLV-1 is a tropical disease that can be transmitted by sexual intercourse, blood transfusion, and breast-feeding. Some infected subjects develop an HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a condition characterized by spasticity, weakness in lower limbs, and difficulty in walking long distances and going up and down the stairs, besides the history of falls. We compared the body oscillations using a force plate to investigate the postural balance control. HTLV-1 infected patients had imbalance that could be identified by posturographic parameters. Patients with HAM/TSP clearly had balance impairments, while HTLV-1 without HAM/TSP had a subtle impairment that was not seen on clinical scales, suggesting that these patients were in the middle between healthy and HAM/TSP patients, and carried a risk of developing severe imbalance postural control. We suggest that more research should be done with the aim to identify the subtle signs in asymptomatic HTLV-1 patients to investigate if this group of patients need attention similar to the HAM/TSP patients.