Tropical Spastic Paraparesis Research Articles

Human T Lymphotropic Virus 1-Associated Myelopathy: Overview of Human T Cell Lymphotropic Virus-1/2 Tests and Potential Biomarkers.

Human T cell lymphotropic virus (HTLV)-1-associated myelopathy is a chronic, disabling inflammatory disorder of the spinal cord caused by HTLV-1 infection. The diagnosis of HTLV-1-associated myelopathy (HAM) is based on clinical and laboratorial findings. The disease is characterized by the presence of spastic paraparesis associated with detection of anti-HTLV-1 antibodies or HTLV-1 genomes in blood and cerebrospinal fluid (CSF). New inflammatory markers have been proposed for the diagnosis and assessment of the prognosis of HAM. We reviewed the laboratory diagnostic and potential surrogate markers for HAM. The serological screening tests for detection of anti-HTLV-1/2 antibodies are highly sensitive and specific, but confirmation and typing of HTLV-1 or HTLV-2 infection by other serological or molecular methods are essential. Detection of intrathecal anti-HTLV-1 antibodies and quantification of the HTLV-1 provirus in CSF provide additional evidence for diagnosis especially in atypical cases or where alternative causes of neuroinflammation cannot be excluded. The CXC motif chemokine ligand 10 and neopterin in serum and CSF are now emerging as inflammatory markers with prognostic value and for HAM monitoring and management. In addition, measures of neurodegeneration, such as neurofilament light chain in the CSF and blood, may also contribute to the HAM prognosis. This review is useful for clinicians and researchers evaluating potential benefits and limitations of each biomarker in clinical practice. The advent of new markers makes it necessary to update the criteria for the best evidence-based approach and for worldwide consensus regarding the use of diagnostic and surrogate markers for HAM.

Phenotypic and functional analysis of γδ T cells in the pathogenesis of human T-cell lymphotropic virus type 1 infection.

The human T-cell leukemia virus type 1 (HTLV-1) is the cause of serious malignant and inflammatory diseases, including adult T-cell leukemia and lymphoma and tropical spastic paraparesis. The potential protective role of γδ T cells in HTLV-1 infection remains unclear. Here, demonstrate that there is a decrease in the amount of Vγ9Vδ2 T cells in patients with HTLV-1, especially in those with HTLV-1 associated pathologies. This suggests that γδ T cells could be involved in controlling the virus. Indeed, we found that Vγ9Vδ2 T cells, expanded from non-infected individuals, can kill cells expressing the viral proteins HBZ and Tax and this phenotype is reversed in the presence of mevastatin. Cytotoxicity by Vγ9Vδ2 T cells was not associated with an increase of INF-γ production. In sharp contrast, killing by NK cells was reduced by Tax expression. Thus, our study provides initial evidence for a potential protective role of Vγ9Vδ2 T cells against HTLV-1 infection. Therapeutic exploitation of these insights is feasible with current technologies of T-cell therapies and could provide novel tools to prevent and treat HTLV-1-associated malignancies and neurologic complications.

HTLV I/II Infection from Blood Donors of GUAYAQUIL – ECUADOR

Background: There are two linfo tropic human virus. The HTLV-1 causes the myelopathy which is linked with the HTLV-1 o Tropical spastic paraparesis (TSP) and Adult T-cell leukemia/lymphoma (ATL or ATLL). Therefore, the HTLV-2 has been related with neurological symptoms similar to the TSP. In Ecuador, there are not updated statistics about HTLV I/II infection.
 Objective: To determine the seroprevalence of HTLV I/II infection in blood donors who attended to the blood bank in the ”Teodoro Maldonado Carbo” Hospital from Guayaquil, Ecuador, from April 2017 to December 2018.
 Materials and methods: The population were twenty-three thousand one hundred ninetyfive (23 195) blood donors. The HTLV I/II antibody detection was done through the Chemiluminescence immunoassay (CLIA) technique.
 Results: From 23 195 blood donors, 0.73% (n = 170) had a reactive or positive result for HTLV I/II antibodies. The 72% of donors (n=122) with a positive result were males and 28% (n = 48) were women. The average age of donors with a positive test result was 40 ± 21 years old. From the 170 reactive donors, 97 (57%) were employed, 51 were unemployed, 16 were farmers end 6 were students. From de full positive result donors, the 87% (n=148) lived in Guayaquil and 22 lived in another cities of Ecuador Conclusions: The seroprevalence of HTLV I/II infection in blood donors who participated in the research at ”Teodoro Maldonado Carbo” Hospital in Guayaquil, is 0.73% (n = 170); it means that for every 137 donors, one has reactive or positive test result. It confirms the importance of preventing the disease transmission through transfused blood.

Refining the risk of HTLV-1-associated myelopathy in people living with HTLV-1: identification of a HAM-like phenotype in a proportion of asymptomatic carriers

Up to 3.8% of human T-lymphotropic virus type-1 (HTLV-1)-infected asymptomatic carriers (AC) eventually develop HTLV-1-associated myelopathy (HAM). HAM occurs in patients with high (> 1%) HTLV proviral load (PVL). However, this cut-off includes more than 50% of ACs and therefore the risk needs to be refined. As HAM is additionally characterised by an inflammatory response to HTLV-1, markers of T cell activation (TCA), β2-microglobulin (β2M) and neuronal damage were accessed for the identification of ACs at high risk of HAM. Retrospective analysis of cross-sectional and longitudinal routine clinical data examining differences in TCA (CD4/CD25, CD4/HLA-DR, CD8/CD25 & CD8/HLA-DR), β2M and neurofilament light (NfL) in plasma in ACs with high or low PVL and patients with HAM. Comparison between 74 low PVL ACs, 84 high PVL ACs and 58 patients with HAM revealed a significant, stepwise, increase in TCA and β2M. Construction of receiver operating characteristic (ROC) curves for each of these blood tests generated a profile that correctly identifies 88% of patients with HAM along with 6% of ACs. The 10 ACs with this ‘HAM-like’ profile had increased levels of NfL in plasma and two developed myelopathy during follow-up, compared to none of the 148 without this viral-immune-phenotype. A viral-immuno-phenotype resembling that seen in patients with HAM identifies asymptomatic carriers who are at increased risk of developing HAM and have markers of subclinical neuronal damage.

Effect of neuromodulation on pain and functional mobility in people with HTLV-1: randomized clinical trial protocol

BACKGROUND: The main symptoms of myelopathy associated with human T-cell lymphotropic virus type 1 or tropical spastic paraparesis (HAM / TSP) are the presence of high intensity pain in the lower back, spasticity and weakness in the lower limbs, loss of balance and difficulties in locomotion. Pulsed Transcranial Magnetic Stimulation (rTMS) has been able to influence cortical plasticity, decreasing spasticity, increasing motor performance and promoting analgesia in several similar conditions. OBJECTIVE: To analyze the effect of neuromodulation by pulsed transcranial magnetic stimulation (rTMS) on pain and functional mobility in individuals with HAM / TSP. METHODOLOGY: A randomized clinical trial will be conducted in a sample made up of 40 participants randomly allocated into two groups: Sham Group (SG) with 20 and Test Group (TG) with 20 patients. Individuals aged> 20 years, community walkers with or without orthosis, with chronic pain (? 6 months) in the lumbar region and / or lower limbs will be included. Individuals with epilepsy, cancer, pregnant women, patients with cardiac pacemakers, metallic implants in the brain or skull, users of illicit drugs and / or use of controlled medications in the last six months will be excluded. The protocol will be applied for 10 consecutive days with eight months of follow-up. Our hypothesis is that when using rTMs according to the proposed procedure, it will be possible to relieve pain and improve the functional mobility of these individuals with a long-lasting effect. CONCLUSION: We hope that rTMS is a promising treatment to reduce pain intensity and to improve functional mobility in individuals undergoing active modality. We declare this protocol a promising resource for the treatment of htlv-1 individuals in reducing pain and improving functional mobility. Yes, this protocol has already been applied to 6 patients. However, with the pandemic the study had to be discontinued. However, despite the small sample size and not being fully applied as suggested by the protocol, it was possible to notice a satisfactory result of the intervention. Thus, the application of this protocol can contribute to identify the result of this therapeutic modality in a safer way, as well as assist in the treatment of symptoms of this population, favoring a better quality of life.

Bioprospection and Selection of Peptides by Phage Display as Novel Epitope-Based Diagnostic Probes for Serological Detection of HTLV-1 and Use in Future Vaccines.

Human T-lymphotropic virus 1 (HTLV-1) is endemic worldwide and the infection results in severe diseases, including Adult T-cell Leukemia (ATL) and HTLV-1 associated myelopathy (HAM). There are some limitations of employing the present commercial serological assays for both diagnostic and epidemiological purposes in different geographical areas of the Brazil, such as the Amazon Region. Currently, methods for diagnosis are usually expensive to adapt for routine use. The aim of this work was to identify and characterize specific ligands to IgG that mimic HTLV-1 epitopes through the Phage Display technique, which could be used for diagnosis and as future vaccine candidates. Initially, IgG from 10 patients with HTLV-1 and 20 negative controls were covalently coupled to protein G-magnetic beads. After biopanning, genetic sequencing, bioinformatics analysis and Phage-ELISA were performed. The technique allowed the identification of 4 clones with HTLV-1 mimetic peptides, three aligned with gp46, A6 (SPYW), B6 (SQLP) and D7 (PLIL), and one with the protease and Tax, A8 (SPPR). Clones A6 and B6 showed higher values of accessibility, antigenicity and hydrophilicity. The reactivity of the clones evaluated by the Receiver Operating Characteristic (ROC) curve showed that the B6 clone had the highest Area Under Curve (0.83) and sensitivity and specificity values (both were 77.27 %; p < 0.001). The study showed that the Phage Display technique is effective for the identification of HTLV-1-related peptides. Clone B6 indicated to be a good marker for bioprospecting diagnostic test for HTLV-1 infection and could be used as a possible vaccine candidate for future studies.

Association of the p75NTR Ser205Leu Polymorphism with Asymptomatic HTLV-1 Infection.

Genetic variations in components of the immune response seem to be an important factor that contributes to the manifestation of symptoms of some diseases related to HTLV-1 infection. Nerve growth factor (NGF) and the p75 neurotrophin receptor (p75NTR) are related to the maintenance of neurons and the activation of the immune response. In this study, we evaluated the association of the NGF -198C/T, NGF Ala35Val, and p75NTR Ser205Leu polymorphisms with HTLV-1 infection and plasma cytokine levels in 166 samples from individuals infected with HTLV-1 (59 symptomatic and 107 asymptomatic). The genotyping and quantification of the proviral load were performed by real-time PCR, and cytokine levels were measured by ELISA. The NGF -198C/T and NGF Ala35Val polymorphisms were not associated with HTLV-1 infection. The frequency of the Ser/Leu genotype of p75NTR Ser205Leu was more frequent in the control group (p = 0.0385), and the Ser/Leu genotype and allele Leu were more frequent among the asymptomatic (p < 0.05), especially with respect to the HTLV-1-associated myelopathy (HAM) group (p < 0.05). The symptomatic showed a higher proviral load and higher TNF-α and IL-10 levels (p < 0.05). Asymptomatic carriers of the Ser/Leu genotype (p = 0.0797) had lower levels of proviral load and higher levels of TNF-α (p = 0.0507). Based on the results obtained, we conclude that the p75NTR Ser205Leu polymorphism may be associated with reduced susceptibility to HTLV-1 infection, a lower risk of developing symptoms, including HAM, and better infection control.

HTLV-1 encephalomyelitis; a case report of a treatable manifestation of HTLV-1 infection

IntroductionHuman T-cell lymphotropic virus type-1 (HTLV-1) infection remains asymptomatic in &gt;90% of the 20-million people infected worldwide. However in 3%, chronic inflammation within the thoracic spinal cord leads to progressive spastic paraparesis; HTLV-1 associated myelopathy (HAM). This pathological process is not limited to the thoracic cord. We present a case of HTLV-1 encephalomyelitis.CaseA 53-year-old woman with HAM of 9 years duration presented with subacute cerebellar dysfunc- tion, being unable to feed herself, 3-months after cessation of methotrexate. Investigations demonstrated extensive T2-hyperintensity within the brainstem, cortical and subcortical white matter with punctate contrast enhancement; lymphocytic CSF; and high blood (36%) and CSF (72%) HTLV-1 proviral load (DNA copies per 100 lymphocytes). We diagnosed HTLV-1 encephalomyelitis and commenced high dose methylprednisolone with slow steroid taper following which functional independence in the upper limbs was regained.DiscussionRisk of HAM rises exponentially once HTLV-1 proviral load exceeds 1%, while CSF:blood proviral load ratio ≥2:1 indicates CNS infiltration of HTLV-1 infected lymphocytes. This patient’s high HTLV-1 proviral load and widespread MRI changes indicated HTLV-1 associated inflammation of the brain and spine. Prompt immunosuppression resulted in significant recovery and highlights the importance of early rec- ognition and management of extraspinal manifestations of HTLV-1 infection.j.king-robson@nhs.net

Mycophenolate Mofetil for the Treatment of HTLV-1 Associated Myelopathy: A Case Report (P11-9.003)

Mycophenolate Mofetil for the Treatment of HTLV-1 Associated Myelopathy: A Case Report (P11-9.003)

Updates on HTLV-1 Uveitis.

HTLV-1 uveitis (HU) is the third clinical entity to be designated as an HTLV-1-associated disease. Although HU is considered to be the second-most frequent HTLV-1-associated disease in Japan, information on HU is limited compared to that on adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). Recent studies have addressed several long-standing uncertainties about HU. HTLV-1-related diseases are known to be caused mainly through vertical transmission (mother-to-child transmission), but emerging HTLV-1 infection by horizontal transmission (such as sexual transmission) has become a major problem in metropolitan areas, such as Tokyo, Japan. Investigation in Tokyo showed that horizontal transmission of HTLV-1 was responsible for HU with severe and persistent ocular inflammation. The development of ATL and HAM is known to be related to a high provirus load and hence involves a long latency period. On the other hand, factors contributing to the development of HU are poorly understood. Recent investigations revealed that severe HU occurs against a background of Graves’ disease despite a low provirus load and short latency period. This review highlights the recent knowledge on HU and provides an update on the topic of HU in consideration of a recent nationwide survey.

Health-Related Quality of Life Evaluation Using the Short Form-36 in Patients With Human T-Lymphotropic Virus Type 1-Associated Myelopathy.

BackgroundHuman 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).MethodsWe 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.ResultsThe 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.ConclusionHRQoL 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.

Occupational Therapy for People Living With Human T-Lymphotropic Virus 1: Importance and Effectiveness of an Intervention Plan at the Level of Prevention and Rehabilitation.

IntroductionHuman T-lymphotropic virus 1 (HTLV-1)-associated myelopathy (HAM) restricts activities of daily living (ADLs), affecting health and quality of life. Occupational therapy is used to promote independence during ADL in people living with HTLV (PLHTLV).ObjectiveTo quantify the clinical aspects, levels of functionality, performance in ADLs and occupational roles of PLHTLV and propose an occupational therapeutic intervention.MethodA cross-sectional, descriptive, observational study was designed with 40 PLHTLV monitored at two referral laboratories of the Federal University of Pará. The Evandro Chagas Research Institute Neurological Disability Scale (EIPEC-2), the Barthel Index and the Occupational Roles Identification List were applied. The G test and Fisher’s exact test (to identify associations between qualitative variables), the Mann–Whitney test (to identify associations between quantitative variables) and Pearson correlation analysis (to identify associations between the total Barthel Index and EIPEC-2 scores) were performed with Microsoft Excel and BioEstat 5.0, and the significance level was set at p ≤ 0.05.ResultsMotor aspects, the presence of spasticity, sensory aspects, and pain in the lumbar region and lower limbs were significantly (p = 0.0002) higher among symptomatic individuals, who also had more difficulties urinating, traveling up and down stairs and transferring from a chair to a bed. Being a worker, performing housework and socializing (with friends or family members) were the most affected activities among HAM patients.ConclusionThe impact of HAM on PLHTLV should include an intervention plan with occupational therapists in rehabilitation programs to create an important third-level prevention initiative, which may help achieve short-, medium-, and long-term goals. Asymptomatic PLHTLV should also be able to prevent future ADL impairment.

Diffusion tensor imaging metrics in diagnosis of HTLV‐1‐associated myelopathy

In the diagnosis of HTLV-1-associated myelopathy (HAM), while magnetic resonance imaging (MRI) is essential to exclude other diseases, its power is limited regarding HAM diagnosis, as only 30% of affected patients present with spinal cord atrophy. Diffusion tensor imaging (DTI) may enable the detection of damage in the white matter microstructure. Here, we quantitatively assess spinal cord damage using DTI and evaluate conventional MRI parameters of the spinal cord in HTLV-1-infected individuals. This cross-sectional study involved 33 HTLV-1 carriers, 28 patients with definite-HAM, and 11 seronegative healthy subjects (HS). Region-of-interest (ROI)-based fractional anisotropy (FA) and mean diffusivity (MD) measurements were performed in the upper thoracic and lumbar regions of the spinal cord. Thoracic index was defined as 1/ (anteroposterior diameter × transverse diameter) measured at the fifth 5th vertebral level. Receiver operating characteristic (ROC) curve analysis was used to determine optimal cutoff FA, MD, and thoracic index values. Spinal cord atrophy was observed in 15 (53.6%) patients with definite-HAM. The area under the ROC curve in the thoracic spinal cord was 0.824 (95% CI, 0.716-0.932), 0.839 (95% CI: 0.736-0.942), and 0.838 (95% CI: 0.728-0.949) for FA, MD, and the thoracic index, respectively. Lower FA and higher MD values were observed in the definite-HAM group compared to HTLV-1 carriers and HS at the T5 vertebral level (p < 0.01). Complementary to conventional MRI, DTI analysis of the spinal cord and thoracic index determination can offer additional insight that may prove useful in the diagnosis of HAM.

Frequency and characteristics of HTLV in migrants: results from the +Redivi collaborative network in Spain.

The objective of this study was to describe the main characteristics of migrants diagnosed with human T-lymphotropic virus (HTLV) infection within the +Redivi Spanish network. Patients with a diagnosis of HTLV type 1 or 2 in +Redivi from October 2009 to December 2020 were included. Diagnosis was based on positive HTLV serology (enzyme-linked immunosorbent assay (ELISA)/chemiluminescent immunoassay (CLIA)) with line immunoassay (LIA)/Western blot with/without polymerase chain reaction (PCR). A total of 107/17 007 cases (0.6%) had a final diagnosis of HTLV infection: 83 (77.67%) HTLV-1 infections, 6 (5.6%) HTLV-2 infections and 18 (16.8%) non-specified. The majority (76, 71%) were female, median age was 42years and median time from arrival to Spain until consultation was 10years. The group included 100 (93.5%) immigrants and 7 (6.6%) visiting friends and relatives (VFR)-immigrants. Most patients were from South America (71, 66.4%), followed by Sub-Saharan Africa (15, 14%) and Central America-Caribbean (13, 12.1%). Around 90% of patients were asymptomatic at presentation and diagnosed as part of screening programs. Median duration of follow-up was 5years (IQR 2-7). Regarding HTLV-associated conditions, 90 patients (84.2%) had none, 7 (6.5%) had tropical spastic paraparesis , 5 (4.7%) had other associated conditions (dermatitis, uveitis, pulmonary disease), 3 (2.8%) had other neurological symptoms and 2 (1.9%) had adult T-cell leukaemia/lymphoma. No patients with HTLV-2 had HTLV-associated conditions. Four patients (3.7%) died. Concomitant diagnoses were found in 41 (38.3%) patients, including strongyloidiasis in 15 (14%) and HIV co-infection in 4 (3.7%). In 70% of patients, screening of potential contacts was not performed/recorded. HTLV infections (the majority due to HTLV-1) were mainly diagnosed in asymptomatic migrants from Latin America (generally long-settled immigrants and the majority female with the consequent implications for screening/prevention). A high rate of association with strongyloidiasis was found. In the majority, screening of potential contacts was not performed, representing a missed opportunity for decreasing the under diagnosis of this infection.

Bladder dysfunction in human T cell lymphotropic virus infection: A prospective cohort study.

BackgroundWhile 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.ObjectiveCompare the severity and evolution of bladder dysfunction in HTLV-1-infected patients with possible and definite HAM/TSP.MethodsThe 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).ResultsAt 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.ConclusionsAlthough 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.

HIV-1 and HTLV-1 Transmission Modes: Mechanisms and Importance for Virus Spread

So far, only two retroviruses, human immunodeficiency virus (HIV) (type 1 and 2) and human T-cell lymphotropic virus type 1 (HTLV-1), have been recognized as pathogenic for humans. Both viruses mainly infect CD4+ T lymphocytes. HIV replication induces the apoptosis of CD4 lymphocytes, leading to the development of acquired immunodeficiency syndrome (AIDS). After a long clinical latency period, HTLV-1 can transform lymphocytes, with subsequent uncontrolled proliferation and the manifestation of a disease called adult T-cell leukemia (ATLL). Certain infected patients develop neurological autoimmune disorder called HTLV-1-associated myelopathy, also known as tropical spastic paraparesis (HAM/TSP). Both viruses are transmitted between individuals via blood transfusion, tissue/organ transplantation, breastfeeding, and sexual intercourse. Within the host, these viruses can spread utilizing either cell-free or cell-to-cell modes of transmission. In this review, we discuss the mechanisms and importance of each mode of transmission for the biology of HIV-1 and HTLV-1.

Monitoring of HTLV-1-associated diseases by proviral load quantification using multiplex real-time PCR.

Proviral load (PVL) is one of the determining factors for the pathogenesis and clinical progression of the human T-lymphotropic virus type I (HTLV-1) infection. In the present study, we optimized a sensitive multiplex real-time PCR for the simultaneous detection and quantification of HTLV-1 proviral load and beta-globin gene as endogenous control. The values obtained for HTLV-1 PVL were used to monitor the clinical evolution in HTLV-1-infected individuals. A vector containing cloned DNA targets of the real-time PCR for the beta-globin gene and the HTLV-1pol region was constructed. For the reaction validation, we compared the amplification efficiency of the constructed vector and MT-2 cell line containing HTLV-1. The analytical sensitivity of the reaction was evaluated by the application of a standard curve with a high order of magnitude. PVL assay was evaluated on DNA samples of HTLV-1 seropositive individuals. The construct showed adequate amplification for the beta-globin and HTLV-1 pol genes when evaluated as multiplex real-time PCR (slope = 3.23/3.26, Y-intercept = 40.18/40.73, correlation coefficient r2 = 0.99/0.99, and efficiency = 103.98/102.78, respectively). The quantification of PVL using the MT-2 cell line was equivalent to the data obtained using the plasmidial curve (2.5 copies per cell). In HTLV-1-associatedmyelopathy/tropical spastic paraparesis patients, PVL was significantly higher (21315 ± 2154 copies/105 PBMC) compared to asymptomatic individuals (1253 ± 691 copies/105 PBMC). The obtained results indicate that the optimized HTLV-1 PVL assay using plasmidial curve can be applied for monitoring and follow-up of the progression of HTLV-1 disease. The use of a unique reference plasmid for both HTLV-1 and endogenous gene allows a robust and effective quantification of HTLV-1 PVL. In addition, the developed multiplex real-time PCR assay was efficient to be used as a tool to monitor HTLV-1-infected individuals.

Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P).

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were −13.8% (95% CI: −20.1–−7.1; p < 0.001) and −6.0% (95% CI: −12.8–1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085)

Does HTLV-1 Infection Show Phenotypes Found in Sjögren's Syndrome?

Viruses are a possible cause for Sjögren’s syndrome (SS) as an environmental factor related to SS onset, which exhibits exocrine gland dysfunction and the emergence of autoantibodies. Although retroviruses may exhibit lymphocytic infiltration into exocrine glands, human T-cell leukemia virus type 1 (HTLV-1) has been postulated to be a causative agent for SS. Transgenic mice with HTLV-1 genes showed sialadenitis resembling SS, but their phenotypic symptoms differed based on the adopted region of HTLV-1 genes. The dominance of tax gene differed in labial salivary glands (LSGs) of SS patients with HTLV 1-associated myelopathy (HAM) and adult T-cell leukemia. Although HTLV-1 was transmitted to salivary gland epithelial cells (SGECs) by a biofilm-like structure, no viral synapse formation was observed. After infection to SGECs derived from SS patients, adhesion molecules and migration factors were time-dependently released from infected SGECs. The frequency of the appearance of autoantibodies including anti-Ro/SS-A, La/SS-B antibodies in SS patients complicated with HAM is unknown; the observation of less frequent ectopic germinal center formation in HTLV-1-seropositive SS patients was a breakthrough. In addition, HTLV-1 infected cells inhibited B-lymphocyte activating factor or C-X-C motif chemokine 13 through direct contact with established follicular dendritic cell-like cells. These findings show that HTLV-1 is directly involved in the pathogenesis of SS.

Cerebral and spinal cord changes observed through magnetic resonance imaging in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis: a systematic review.

To verify brain and spinal changes using magnetic resonance imaging in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. This was a systematic review. The descriptors used were tropical spastic paraparesis and magnetic resonance image. The keyword HTLV-1-associated myelopathy was also used. Twenty-three articles were included: 16 detected brain changes and 18 detected spinal changes. White matter lesions were the most frequent finding in the brain. Brain injuries were most frequently identified in the periventricular region, in the subcortical region, in the centrum semiovale, in the brain stem, and corpus callosum. Atrophy was the most frequent finding of the spinal cord, affecting the thoracic and cervical regions, and was associated with a longer evolution of myelopathy. White matter lesions in these regions were also observed. Cortical white matter lesions and thoracic spinal cord atrophy were the most frequently reported changes in patients with HTLV-1-associated myelopathy.