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

Health state utility values in people living with HTLV-1 and in patients with HAM/TSP: The impact of a neglected disease on the quality of life.

Background: HTLV-1 is a neglected sexually transmitted infection despite being the cause of disabling neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is no treatment for this infection and public health policies are essential to reduce its transmission. However, there are no data to support adequate cost-effective analysis in this field. The aim of this study was to obtain health state utility values for individuals with HAM/TSP and HTLV-1 asymptomatic carriers (AC). The impact of both states on quality of life (QoL) is described and compared to other diseases. Methods: A cross-sectional observational study of 141 individuals infected with HTLV-1 (79 with HAM/TSP and 62 AC) from three Brazilian states (Rio de Janeiro, São Paulo and Alagoas) and from the United Kingdom. Participants completed a validated general health questionnaire (EQ-5D, Euroqol) from which country specific health state utility values are generated. Clinical and epidemiological data were collated. Principal findings: Health state utility value for HAM/TSP was 0.2991. QoL for 130 reported clinical conditions ranges from 0.35 to 0.847. 12% reported their quality of life as worse as death. Low QoL was associated with severity rather than duration of disease with a moderate inverse correlation between QoL and Osame’s Motor Disability Score (-0.4933) Patients who are wheelchair dependent had lowest QoL whilst those still walking unaided had the highest. AC also reported impaired QoL (0.7121) compared to general population. Conclusion: HTLV-1 and its associated neurological disease has a marked impact on QoL. This study provides robust data to support the development of cost-utility analysis of interventions for HTLV-1.

Status of humoral and cellular immune markers in human T-cell lymphotropic virus type 1 (HTLV-1) asymptomatic carriers in northeastern Iran, Mashhad.

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

Microbial Biofilms: Human T-cell Leukemia Virus Type 1 First in Line for Viral Biofilm but Far Behind Bacterial Biofilms

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). To date, it is the unique published example of a virus able to form a biofilm at the surface of infected cells. Deeply studied in bacteria, bacterial biofilms represent multicellular assemblies of bacteria in contact with a surface and shielded by the extracellular matrix (ECM). Microbial lifestyle in biofilms, either viral or bacterial, is opposed structurally and physiologically to an isolated lifestyle, in which viruses or bacteria freely float in their environment. HTLV-1 biofilm formation is believed to be promoted by viral proteins, mainly Tax, through remodeling of the ECM of the infected cells. HTLV-1 biofilm has been linked to cell-to-cell transmission of the virus. However, in comparison to bacterial biofilms, very little is known on kinetics of viral biofilm formation or dissemination, but also on its pathophysiological roles, such as escape from immune detection or therapeutic strategies, as well as promotion of leukemogenesis. The switch between production of cell-free isolated virions and cell-associated viral biofilm, although not fully apprehended yet, remains a key step to understand HTLV-1 infection and pathogenesis.

A novel positive feedback-loop between the HTLV-1 oncoprotein Tax and NF-\u03baB activity in T-cells

BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) infects primarily CD4+ T-lymphocytes and evoques severe diseases, predominantly Adult T-Cell Leukemia/ Lymphoma (ATL/L) and HTLV-1-associated Myelopathy/ Tropical Spastic Paraparesis (HAM/TSP). The viral transactivator of the pX region (Tax) is important for initiating malignant transformation, and deregulation of the major signaling pathway nuclear factor of kappa B (NF-κB) by Tax represents a hallmark of HTLV-1 driven cancer.ResultsHere we found that Tax mutants which are defective in NF-κB signaling showed diminished protein expression levels compared to Tax wildtype in T-cells, whereas Tax transcript levels were comparable. Strikingly, constant activation of NF-κB signaling by the constitutive active mutant of inhibitor of kappa B kinase (IKK2, IKK-β), IKK2-EE, rescued protein expression of the NF-κB defective Tax mutants M22 and K1-10R and even increased protein levels of Tax wildtype in various T-cell lines while Tax transcript levels were only slightly affected. Using several Tax expression constructs, an increase of Tax protein occurred independent of Tax transcripts and independent of the promoter used. Further, Tax and M22 protein expression were strongly enhanced by 12-O-Tetradecanoylphorbol-13-Acetate [TPA; Phorbol 12-myristate 13-acetate (PMA)]/ ionomycin, inducers of NF-κB and cytokine signaling, but not by tumor necrosis factor alpha (TNF-α). On the other hand, co-expression of Tax with a dominant negative inhibitor of κB, IκBα-DN, or specific inhibition of IKK2 by the compound ACHP, led to a vast decrease in Tax protein levels to some extent independent of Tax transcripts in transiently transfected and Tax-transformed T-cells. Cycloheximide chase experiments revealed that co-expression of IKK2-EE prolongs the half-life of M22, and constant repression of NF-κB signaling by IκBα-DN strongly reduces protein stability of Tax wildtype suggesting that NF-κB activity is required for Tax protein stability. Finally, protein expression of Tax and M22 could be recovered by NH4Cl and PYR-41, inhibitors of the lysosome and the ubiquitin-activating enzyme E1, respectively.ConclusionsTogether, these findings suggest that Tax’s capability to induce NF-κB is critical for protein expression and stabilization of Tax itself. Overall, identification of this novel positive feedback loop between Tax and NF-κB in T-cells improves our understanding of Tax-driven transformation.

Clinical profile of human T-lymphotropic virus type I: a forgotten infection in pediatrics

The Human T-lymphotropic virus type 1 (HTLV-1), a retrovirus with oncogenic properties, affects around ten to twenty million people worldwide. The most common disorders associated with HTLV-1 infection are T-cell leukemia/lymphoma (ALT) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Studies have reported other clinical manifestations in HTLV-1 seropositive patients, including inflammatory disorders, co-infections with opportunistic agents, and pulmonary diseases. Objective: Here, we aim to describe a cohort of juvenile patients with confirmed HTLV-1 infection that showed clinical manifestations other than neurological symptoms. Methodology and patients: Retrospective analysis of clinical data describing background and clinical findings of 12 juvenile patients with confirmed HTLV-1 infection, attended during January 2018 to February 2020 in a pediatric referral hospital in Cali, Colombia. Results: 11 out 12 patients were from Colombia´s Pacific coast, 10 suffered from significant nutritional deficiencies. Six exhibited dermatological findings, 3 compatible with infective dermatitis. None of the cases exhibited clinical or laboratory findings suggesting ALT or HAM/TPS. Eight patients had structural lung disease assessed by chest Computed Tomography (CT) scans; 4 of them tested positive for galactomannan antigen in bronchoalveolar fluid suggesting pulmonary aspergillosis, and 2 others exhibited a positive PCR testing for tuberculosis. Three patients were diagnosed with autoimmune disorders; 1 patient with Crohn´s Diseases, 1 case of autoimmune thrombocytopenic purpura, and a patient with Vogt-Koyanagi-Harada syndrome (non-granulomatous uveitis). Conclusions: There is a broad range of clinical manifestations in pediatric HTLV-1 patients, and the clinician should consider structural pulmonary disease, opportunistic co-infections and autoimmune disorders in the diagnostic algorithm.

HLA-B*35 as a new marker for susceptibility to human T-cell lymphotropic virus type 1 (HTLV-1) Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in patients living in Argentina

BackgroundHuman 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.ResultsThe 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.ConclusionsWe 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.

CD49d Is Upregulated in Circulating T Lymphocytes from HTLV-1-Infected Patients

Introduction: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic progressive myelopathy associated with an inflammation of the central nervous system (CNS), being characterized by perivascular infiltration of inflammatory cells. HTLV-1-infected cells have the capacity to migrate through endothelial layers by enhancing adhesion receptor expression and corresponding ligands. T cells interact with the extracellular matrix via integrin receptors and these interactions affect both cell migration and proliferation. The importance of these interactions in retrovirus-induced diseases, however, remains less clear. Methods: Herein we studied the expression of 3 integrin alpha chains (CD49d, CD49e, and CD49f) on the membrane of T-cell subsets in patients infected by HTLV-1, both HAM/TSP patients and oligo/asymptomatic subjects who were asymptomatic or presented slight manifestations related to the virus infection. Results: We observed higher peripheral blood frequency of CD49d^hiCD4⁺ and CD49d^hiCD8⁺ T cells in HTLV-1-infected patients. Conclusion: Our findings suggest that the increased expression of adhesion molecules, such as CD49d on T lymphocytes from HTLV-1-infected patients may contribute to the pathogenesis of the disease, in both oligo/asymptomatic and HAM/TSP-infected subjects. Accordingly, it is conceivable that there is a potential use of CD49d as target for a therapeutic approach aiming at blocking migration of activated T cells from HTLV-1-infected patients into the CNS, thus avoiding the progression to HAM/TSP.

Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.

Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that the ABL1 is an important gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whether ABL1 is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, ABL1 siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.

Creation and validation of a bladder dysfunction symptom score for HTLV-1-associated myelopathy/tropical spastic paraparesis

BackgroundUrinary dysfunction is one of the main features of human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, a comprehensive assessment of the severity is difficult because a standardized assessment measure is unavailable. Therefore, this study aimed to develop a novel symptom score for the assessment of urinary dysfunction in HAM/TSP. We interviewed 449 patients with HAM/TSP using four internationally validated questionnaires for assessment of urinary symptoms (27 question items in total): the International Prostate Symptom Score; the International Consultation on Incontinence Questionnaire-Short Form; the Overactive Bladder Symptom Score; and the Nocturia Quality-of-Life questionnaire. We developed a symptom score based on the data of 322 patients who did not use urinary catheters by selecting question items from questionnaires focused on descriptive statistics, correlation analysis, and exploratory factor analysis. The score distribution, reliability, and validity of the developed score were evaluated.ResultsFirst, 16 questions related to quality of life, situations, or subjective assessment were omitted from the 27 questions. Exploratory factor analysis revealed that the remaining 11 questions pertained to three factors: frequent urination, urinary incontinence, and voiding symptoms. Three questions, which had similar questions with larger factor loading, were deleted. Finally, we selected eight question items for inclusion in the novel score. The score distribution exhibited no ceiling or floor effect. The Cronbach’s alpha (0.737) demonstrated reliable internal consistency. The new score comprised two subscales with acceptable factorial validity (inter-factor correlation coefficient, 0.322): storage symptoms (frequent urination plus urinary incontinence) and voiding symptoms. The correlation between each item and the subscales suggested acceptable construct validity.ConclusionsWe developed a novel score, the HAM/TSP-Bladder Dysfunction Symptom Score, and demonstrated its reliability and validity. The applicability of this score to patients using catheters should be examined in future research.

Phylogenetic and phylodynamic study of Human T-cell lymphotropic virus Type 1 (HTLV-1) in Iran

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).

517 Leveraging CRISPR-Cas12a for the detection of human T-cell leukemia virus type 1

Human T-cell Leukemia Virus type 1 (HTLV-1) is a potent carcinogenic oncovirus that, while asymptomatic in the majority, has the potential to cause devastating complications such as adult T cell leukemia/lymphoma (ATLL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Despite its global burden, poor access to current testing modalities limits HTLV-1 screening in endemic regions. Here we perform pre-clinical experiments that demonstrate the potential for a sensitive, specific, and low-cost CRISPR-based screening test for HTLV-1.

Early-Onset HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

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.

Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1–associated myelopathy/tropical spastic paraparesis

Human T cell leukemia virus 1 (HTLV-1) causes the functionally debilitating disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as adult T cell leukemia lymphoma (ATLL). Although there were concerns that the mortality of HAM/TSP could be affected by the development of ATLL, prospective evidence was lacking in this area. In this 5-y prospective cohort study, we determined the mortality, prevalence, and incidence of ATLL in 527 HAM/TSP patients. The standard mortality ratio of HAM/TSP patients was 2.25, and ATLL was one of the major causes of death (5/33 deaths). ATLL prevalence and incidence in these patients were 3.0% and 3.81 per 1,000 person-y, respectively. To identify patients at a high risk of developing ATLL, flow cytometry, Southern blotting, and targeted sequencing data were analyzed in a separate cohort of 218 HAM/TSP patients. In 17% of the HAM/TSP patients, we identified an increase in T cells positive for cell adhesion molecule 1 (CADM1), a marker for ATLL and HTLV-1-infected cells. Genomic analysis revealed that somatic mutations of HTLV-1-infected cells were seen in 90% of these cases and 11% of them had dominant clone and developed ATLL in the longitudinal observation. In this study, we were able to demonstrate the increased mortality in patients with HAM/TSP and a significant effect of ATLL on their prognosis. Having dominant clonal expansion of HTLV-1-infected cells with ATLL-associated somatic mutations may be important characteristics of patients with HAM/TSP who are at an increased risk of developing ATLL.

Clinicopathological aspects and proviral load of adulthood infective dermatitis associated with HTLV-1: Comparison between juvenile and adulthood forms.

BackgroundInfective dermatitis associated with human T-cell lymphotropic virus type-1 (HTLV-1), (IDH), is a chronic eczema occurring in HTLV-1 infected children. Rare cases of adulthood IDH have been reported and no study until now aimed to compare juvenile and adulthood IDH.Methodology/Principal findingsTwelve cases of adulthood IDH followed for a mean time of 7.5 years were analyzed according to clinicopathological and molecular aspects, comparing them to juvenile IDH cases. Diagnosis was based on the modified major criteria used for juvenile IDH. Proviral load (PVL) assessment was performed by real-time PCR technique. Adulthood IDH presented similar clinicopathological and molecular aspects compared to juvenile IDH. The morphology of lesions and areas of involvement were similar, except for the involvement of the ankles and inframammary folds in the adulthood form. HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) occurred in six adulthood IDH patients, with almost equal frequency. However, at least in two patients, HAM/TSP appeared prior to IDH, differently from what was observed in juvenile IDH.Conclusions/SignificanceAdulthood IDH is similar to juvenile IDH according to clinicopathological aspects and PVL levels. Therefore, the same modified major diagnostic criteria for juvenile IDH can be applied to both forms.

Expression of TSLC1 in patients with HAM/TSP.

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

The IL-18, IL-12, and IFN-γ expression in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, HTLV-1 carriers, and healthy subjects.

Interleukin (IL)-12, IL-18, and interferon gamma (IFN-γ) can induce Th1-inflammatory responses in favor of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) manifestation. In this study, the gene expression and plasma levels of these cytokines were evaluated. The peripheral blood mononuclear cells (PBMCs) in 20 HAM/TSP patients, 21 asymptomatic carriers (ACs), and 21 healthy subjects (HSs) were assessed for the expression of IL-18, IL-12, and IFN-γ, using qRT-PCR. The plasma level of IL-18 and IFN-γ were measured by an ELISA method. The mean of HTLV-1 proviral load (PVL) in the HAM/TSPs was 1846.59 ± 273.25 and higher than ACs at 719.58 ± 150.72 (p = 0.001). The IL-12 was considerably expressed only in nine ACs, five HAM/TSPs, and all HSs. Furthermore, the gene expression and plasma levels of IL-18 were lower in the HTLV-1-positive group than the control group (p = 0.001 and 0.012, respectively); however, there was no significant difference between the ACs and HAM/TSPs. The IFN-γ level was higher in the HTLV-1-positive group (p < 0.001) than HSs. Although there were no correlation between plasma levels of IL-18 and IFN-γ with PVL in the ACs, a positive correlation was observed between plasma IL-18 levels and PVL (r = 0.654, p = 0.002). The highest levels of IFN-γ were observed in the HAM/TSPs which has a significant correlation with HTLV-1-HBZ (r = 0.387, p = 0.05) but not with Tax. However, no significant correlation was found between PVL and proinflammatory pattern. Apart from the IFN-γ as a lymphokine, as a host factor, and HTLV-1-HBZ, as a viral agent, the other proinflammatory monokines or HTLV-1 factors are among the less-effective agents in the maintenance of HAM/TSP.

Management of HAM/TSP: Systematic Review and Consensus-based Recommendations 2019.

Purpose of ReviewTo provide an evidence-based approach to the use of therapies that are prescribed to improve the natural history of HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP)—a rare disease.Recent FindingsAll 41 articles on the clinical outcome of disease-modifying therapy for HAM/TSP were included in a systematic review by members of the International Retrovirology Association; we report here the consensus assessment and recommendations. The quality of available evidence is low, based for the most part on observational studies, with only 1 double-masked placebo-controlled randomized trial.SummaryThere is evidence to support the use of both high-dose pulsed methyl prednisolone for induction and low-dose (5 mg) oral prednisolone as maintenance therapy for progressive disease. There is no evidence to support the use of antiretroviral therapy. There is insufficient evidence to support the use of interferon-α as a first-line therapy.

The Role of Chemokines in the Pathogenesis of HTLV-1.

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.

Clinical significance of soluble CADM1 as a novel marker for adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/leukemia (ATLL) is an aggressive peripheral T-cell malignancy, caused by infection with the human T-cell leukemia virus type 1 (HTLV-1). We recently showed that the cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, is specifically and consistently overexpressed in ATLL cells, and functions as a novel cell surface marker. In this study, we first show that a soluble form of CADM1 (sCADM1) is secreted from ATLL cells by mainly alternative splicing. After developing the Alpha linked immunosorbent assay (AlphaLISA) for sCADM1, we show that plasma sCADM1 concentrations gradually increased during disease progression from indolent to aggressive ATLL. Although other known biomarkers of tumor burden such as soluble interleukin-2 receptor α (sIL-2Rα) also increased with sCADM1 during ATLL progression, multivariate statistical analysis of biomarkers revealed that only plasma sCADM1 was selected as a specific biomarker for aggressive ATLL, suggesting that plasma sCADM1 may be a potential risk factor for aggressive ATLL. In addition, plasma sCADM1 is a useful marker for monitoring response to chemotherapy as well as for predicting relapse of ATLL. Furthermore, the change in sCADM1 concentration between indolent and aggressive type ATLL was more prominent than the change in the percentage of CD4+CADM1+ ATLL cells. As plasma sCADM1 values fell within normal ranges in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients with higher levels of serum sIL-2Rα, the measurement of sCADM1 may become a useful tool to discriminate between ATLL and other inflammatory diseases, including HAM/TSP.

HTLV-1 Infection and Rheumatic Diseases.

Some major research and clinical questions about human T-cell leukemia virus type 1 (HTLV-1) infection and rheumatic diseases remain: (1) Does HTLV-1 infection cause rheumatic diseases? (2) Do patients with rheumatic diseases display different responses to treatment with anti-rheumatic agents when they are HTLV-1 carriers? (3) Is adult T-cell leukemia/lymphoma (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) more prevalent in HTLV-1 carriers with rheumatic diseases who are treated with anti-rheumatic agents? These questions are important because increasing numbers of patients with rheumatic diseases are currently receiving treatment with aggressive medicines such as immunosuppressants and biologics. Studies on HTLV-1 gene-transgenic mice have shown manifestations resembling rheumatic diseases. Epidemiological studies have shown a high incidence of HTLV-1 infection in patients with rheumatic diseases including rheumatoid arthritis (RA), Sjogren’s syndrome, and polymyositis. HTLV-1-positive and HTLV-1-negative patients with RA have displayed similar immunological features including the seroprevalence of anti-citrullinated peptide antibodies. Conversely, attenuated effectiveness of tumor necrosis factor inhibitors for HTLV-1-positive patients with RA in Japan has been reported. Therefore, although no direct evidence has shown that HTLV-1 infection alone causes rheumatic diseases, HTLV-1 may affect the inflammation of RA. Although the incidence of ATL or HAM/TSP among patients with rheumatic diseases has not been investigated in large-scale studies, ATL or HAM/TSP has developed among HTLV-1-positive patients with rheumatic diseases. HTLV-1 infection may affect the clinical course of patients with rheumatic diseases, particularly after receiving anti-rheumatic agents. Because studies on these issues are limited, further investigation with large sample sizes is necessary.