Tropical Spastic Paraparesis Research Articles

Examination of a Reporter Vector for HTLV-1 Infectivity Using MT2, a HTLV-1 Producer Cell Line

Background: HTLV-1 (Human T_cell lymphotropic virus type 1), with about 20 million individuals infected worldwide, is a global health problem that is endemic in certain areas such as Japan and Khorasan province of Iran.HTLV-1 is the causative agent of progressive diseases, Adult T cell Leukemia (ATL), and HTLV-I Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), which do not yet have approved effective treatment. Due to the non-cytolytic characteristic of this virus and cell associated properties, there is no routine Procedure for drug study in vitro and it's confined to some HTLV infected cell lines. Therefore construction of a reporter vector is necessary to evaluate HTLV-1 infectivity in cell culture for drug studies, since designed reporters for retroviruses are usually based on long terminal repeat (LTR) transactivation. LTR region of HTLV-1 contains a virus promoter that plays the most important role in replication and transcription by the Tax transactivation effect. Objectives: In this project we attempted to construct a reporter vector containing the luciferase gene coupled to the HTLV-1 promoter for evaluation of HTLV-1 infectivity. Material and Methods: LTR region was digested from pUCLTR-Lac by HindIII and sub-cloned into the Multiple cloning site (MCS) region of a promoter-less reporter vector, pGL4.17, upstream to the luciferase gene. Colonies were screened by Colony PCR, then selected colonies were confirmed by restriction enzyme digestion and sequencing. Human embryonic kidney (HEK) 293T cell line was transfected by a recombinant vector and inducible expression of luciferase was evaluated. Results: Recombinant vector, pGL4LTR-Luc, has expression levels of more than 50 folds compared to the control when co-transfected with the Tax expressing vector into HEK 293T cells. Moreover, cells display more than 30 folds of luciferase expression over 2 days when cocultured with MT2 cell, a HTLV-1 producer cell line. Conclusions: According to the high functionality of the produced recombinant vector, it seems a good applicable tool for making an indicator cell line in subsequent basic and drug studies.

Association between urinary symptoms and quality of life in HTLV-1 infected subjects without myelopathy

To investigate the relationship between urinary symptoms and quality of life of patients infected with HTLV-1. This is a cross-sectional study that enrolled individuals with HTLV-1 positive serology from February 2010 to March 2011. Participants were HTLV-1 infected subjects followed in the HTLV-1 clinic of the University Hospital in Salvador, Bahia, Brazil. Patients with HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM/TSP), who had evidence of other neurological diseases, diabetes mellitus or were pregnant were excluded from the study. The questionnaire SF-36 was used to evaluate quality of life and the questionnaire OAB-V8 was used to evaluate urinary symptoms. From the 118 individuals evaluated, 50 (42.4%) complained of urinary symptoms and 68 (57.6%) did not. Most participants were females. There was no difference between the groups regarding demographic variables. The group with symptoms showed significantly lower scores in all domains of the SF-36 questionnaire. The domains with greatest differences were vitality and general health state. Urinary symptoms negatively influence the quality of life of individuals infected with HTLV-1.

Dermatological manifestations of individuals infected with human T cell lymphotropic virus type I (HTLV‐I)

Human T cell lymphotropic virus type I (HTLV-I) is associated with specific manifestations such as adult T cell lymphoma/leukemia (ATLL), HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-I-associated uveitis, and infective dermatitis associated with HTLV-I (IDH). Although ATLL and IDH are considered specific manifestations of HTLV-I infection, several dermatological manifestations have been described in HTLV-I seropositive patients. This study was conducted to determine the prevalences of skin lesions in patients infected with HTLV-I in an area of Brazil endemic for HTLV-I infection and to compare these prevalences with those in seronegative individuals in the same region. A prevalence study was conducted between 2008 and 2010 with two groups of individuals comprising, respectively, 179 HTLV-I seropositive (positive enzyme-linked immunosorbent assay [ELISA] and positive Western blot analysis) and 193 HTLV-I seronegative individuals (ELISA-negative). The subjects were selected on a random basis and evaluated using a questionnaire to obtain epidemiological and clinical data. A physical examination was performed to verify the presence of skin lesions. Superficial mycoses were found in 54 (30.2%) seropositive subjects and in 26 (13.5%) of the seronegative group (P<0.001). Xerosis was found in 39.1% of HTLV-I infected subjects and in 9.3% of seronegative controls (P<0.001). Ichthyosis was diagnosed in nine (5.0%) HTLV-I seropositive subjects but in none of the control group (P=0.001). A diagnosis of seborrheic dermatitis was made in 43 (24.0%) HTLV-I infected subjects and in 24 (12.4%) seronegative controls (P=0.004). Furthermore, dermatological manifestations were more intense in the HTLV-I seropositive group. Several dermatological manifestations are more common and more severe in HTLV-I seropositive subjects. The presence of these manifestations in an area endemic for HTLV-I infection may provide some clues in the investigation of this infection.

Soluble IL-2 receptor and beta-2 microglobulin as possible serologic markers of neurologic disease in HTLV-1 infection

The human T-cell leukemia virus (HTLV-1) is the causative agent of a variety of neurologic diseases, including HTLV-1 Associated Myelopathy (HAM/TSP) and overactive bladder. Investigation of immune markers such as soluble interleukin-2 receptor (sIL-2R) and beta-2 microglobulin (B2M) has shown some promising results in distinguishing patients with neurologic disease from those with carrier status. The objective of the present study was to determine if plasma levels of sIL-2R and B2M are markers of neurologic disease in individuals infected with HTLV-1. The present study was divided into two parts. A cross-sectional study and a nested case control study. In the cross-sectional study, HAM/TSP patients had higher plasma levels of B2M and sIL-2R than patients with overactive bladder and HTLV-1 carriers (P < 0.01 for all comparisons). For the nested case control study, the sIL-2 receptor test was able to distinguish patients with HAM/TSP from patients in the combined group of carriers and patients with overactive bladder with a sensitivity of 75.8% and false positive rate of 25.4%. Plasma levels of these markers did not change with the development of HAM/TSP and overactive bladder in HTLV-1 carrier patients. The present study has shown the importance of sIL-2 receptor in helping identifying HAM/TSP. However, the levels of these makers did not change significantly with the development of neurologic disease.

How human T-cell leukemia virus type 1 induces diseases

Human T-cell leukemia virus type1 (HTLV-1) is the causal agent of adult T-cell leukemia (ATL), and inflammatory diseases, such as HTLV-1 associated myelopathy (HAM), uveitis, alveolitis and infective dermatitis. Approximately, 5% of carrier will develop ATL after a long latent period. A characteristic of this virus is that HTLV-1 can transmit only by cell-to-cell contact. Therefore, HTLV-1 increases infected cells in vivo to facilitate its transmission. Previous studies suggest that Tax plays central roles in leukemogenesis by HTLV-1. However, Tax expression is frequently impaired in ATL cells. The HTLV-1 bZIP factor (HBZ) gene is transcribed from minus strand of provirus using 3’ long terminal repeat (LTR) as the promoter/ enhancer. Among ATL cases, only the HBZ gene is expressed in all ATL cases, suggesting an importance of the HBZ gene in ATL cells. Indeed, transgenic expression of the HBZ gene induced T-cell lymphoma and inflammatory diseases. Furthermore, regulatory T (Treg) cells increased in HBZ-transgenic (HBZ-Tg) mice. As a mechanism, HBZ induces transcription of the Foxp3 gene through enhanced Smad/ TGF-β pathway and converts infected cells to Treg cells. Concurrently, HBZ impairs function of Treg via interaction of HBZ with Foxp3 and associated factors. Thus, HBZ increases functionally impaired Treg cells in vivo, which resembles to phenotype of HTLV-1 infected cells and ATL cells. It is speculated that HTLV-1 infected Treg cells escape the host immune surveillance by acquired phenotype of Treg cells. Treg cells derived from HBZ-Tg mice progressively lost Foxp3 expression in vitro and produced IFN-γ, indicating that HBZ induces inflammation through unstable Foxp3 expression. Thus, HBZ is responsible for both T-cell lymphoma and inflammatory diseases. HBZ has pleiotropic functions as well as Tax. HBZ enhances TGF-β/Smad pathway while Tax inhibits it. Likewise, HBZ suppresses canonical NF-κB whereas Tax activates canonical and noncanonical NF-κB pathways. Thus, HBZ has opposite effects to Tax in many pathways. Interplay between HBZ and Tax likely coordinates to promote viral replication and proliferation of infected cells, leading to important roles in the pathogenesis.

Efficacy of prosultiamine treatment in patients with human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis: results from an open-label clinical trial

BackgroundHuman T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy characterized by motor dysfunction of the lower extremities and urinary disturbance. Immunomodulatory treatments are the main strategy for HAM/TSP, but several issues are associated with long-term treatment. We conducted a clinical trial with prosultiamine (which has apoptotic activity against HTLV-I-infected cells) as a novel therapy in HAM/TSP patients.MethodsWe enrolled 24 HAM/TSP patients in this open-label clinical trial. Prosultiamine (300 mg, orally) was administered once daily for 12 weeks. We monitored changes in the motor function of the lower extremities and urinary function as well as copy numbers of the HTLV-I provirus in peripheral blood mononuclear cells (PBMCs).ResultsImprovement in the motor function of the lower extremities based on a reduction in spasticity (for example, decrease in time required for walking and descending a flight of stairs) was observed. In an urodynamic study (UDS), bladder capacity and detrusor pressure and then maximum flow rate increased significantly. Detrusor overactivity and detrusor-sphincter dyssynergia improved in 68.8% and 45.5% of patients observed at pretreatment, respectively. Improvement in UDS corresponded with improvements in the score of nocturia-quality of life questionnaire. HTLV-I proviral copy numbers in PBMCs decreased significantly (approximately 15.4%) compared with pretreatment levels.ConclusionsThese data suggest that prosultiamine can safely improve motor dysfunction of the lower extremities and urinary disturbance as well as reduce HTLV-I provirus levels in peripheral blood. It therefore has potential as a new therapeutic tool for HAM/TSP patients.Trial registration University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number, UMIN000005969. Please see related commentary: http://www.biomedcentral.com/1741-7015/11/183.

Therapeutic benefits of an oral vitamin B1 derivative for human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

Prosultiamine, a vitamin B1 derivative, has long been used for beriberi neuropathy and Wernicke’s encephalopathy. Based on the finding that prosultiamine induces apoptosis in human T lymphotropic virus type I (HTLV-I)-infected T cells, Nakamura et al. conducted a clinical trial of prosultiamine in patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). In this open-label, single arm study enrolling 24 HAM/TSP patients recently published in BMC Medicine, oral prosultiamine (300 mg/day for 12 weeks) was found to be effective by neurological, urological and virological evaluations. Notably, it increased detrusor pressure, bladder capacity and maximum flow rate, and improved detrusor overactivity and detrusor-sphincter dyssynergia. A significant decrease in HTLV-I copy numbers in peripheral blood following the treatment provided a rationale for using the drug. The trial has some limitations, such as the small numbers of participants, the open-label design, the lack of a placebo arm, and the short trial period. Nevertheless, the observation that such a safe, cheap drug may have excellent therapeutic effects on HAM/TSP, a chronic devastating illness occurring mainly in developing countries, provides support for future large-scale randomized controlled trials.Please see related research: http://www.biomedcentral.com/1741-7015/11/182.

CD4+ T cell subsets and Tax expression in HTLV-1 associated diseases

Human T lymphotropic virus type 1 (HTLV-1) infection displays variable clinical manifestations. These include inflammatory diseases such as HTLV-1 associated myelopathy (HAM) or immunosuppressive conditions such as Strongyloides stercoralis hyperinfection. The viral protein, Tax causes activation and proliferation of T cells. We hypothesize that the expression of Tax in T cell subsets characterizes the clinical manifestations of HTLV-1. To test this hypothesis, we measured T helper 1 effector cells and regulatory T cells (Tregs) among Tax expressing lymphocytes from peripheral blood mononuclear cells (PBMCs) of 32 HTLV-1 infected patients with HAM, with S. stercoralis co-infection or with asymptomatic infection. We observed increased ratios of Th1/Treg among Tax expressing lymphocytes in HAM patients. These data suggest that the expression of Tax among the different target cells may explain the variable presentation of HTLV-1.

Incidence of Human T Cell Lymphotropic Virus Type 1-Associated Myelopathy/Tropical Spastic Paraparesis in a Long-Term Prospective Cohort Study of Initially Asymptomatic Individuals in Brazil

The incidence of human T cell lymphotropic virus type 1 (HLTV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is not well defined in the literature. Several studies have reported different incidence rates, and recent publications suggest a higher incidence and prevalence of HAM/TSP. The interdisciplinary HTLV Research Group (GIPH) is a prospective open cohort study of individuals infected with HTLV-1/2. This study describes the demographic data and HAM/TSP incidence rate observed in 181 HTLV-1-seropositive individuals and compares the results with previous reports in the literature. HAM/TSP was diagnosed on the basis of the World Health Organization diagnostic criteria and De Castro-Costa et al. [Proposal for diagnostic criteria of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). AIDS Res Hum Retroviruses 2006;22:931-935]. Seven HAM/TSP incident cases were observed during the follow-up. The HAM/TSP incidence density was 5.3 cases per 1,000 HTLV-1-seropositive cases per year (95% confidence interval: 2.6-10.9), with a mean follow-up of 7±4 years (range: 1 month to 15 years). HAM/TSP was more frequent in women in their 40s and 50s with probable infection via the sexual route. The HAM/TSP incidence density among HTLV-1-seropositive cases observed in the present study is higher than that in previous studies. HAM/TSP may be underdiagnosed in countries like Brazil where HTLV infection is prevalent. Orientation and prevent transmission of HTLV programs are needed. Currently, preventing HTLV-1 transmission is the most effective way to reduce the impact of HAM/TSP on society.

Use of diagnostic and therapeutic biomarkers in personalized oncology based on adult T-cell leukemia/lymphoma research

Abstract Human T-lymphotropic virus type 1 (HTLV-1) infection is linked to a spectrum of diverse diseases, including adult T-cell leukemia/lymphoma (ATLL) and the chronic neuromyelopathy tropical spastic paraparesis or HTLV-1 associated myelopathy (TSP/HAM). ATLL is a neoplasm of mature CD4 + T-cell origin known to be resistant to standard anti-cancer therapies. Based on ATLL research performed in our laboratory as well as other reports, we discuss diagnostic, predictive, and pharmacological biomarkers for companion diagnostics, which are vital factors for personalized oncology. From the viewpoint of resistance to apoptosis, the FAS ligand/FAS system, TRAIL/TRAIL receptor system, and survivin are promising targets for cancer therapy. The tumor suppressor genes p16 INK4a , p14 ARF , and p53 are well known predictive and pharmacological biomarkers for various cancers as well as for ATLL. We have found that the plasma miRNAs miR-155 and miR-126 have importance as novel biomarkers to evaluate disease progression and prognosis in ATLL patients. Furthermore, ATLL is considered an appropriate target disease for epigenetic therapy. Although several molecular diagnostic methods for cancer have been approved over the past decade, only a small number of predictive biomarkers have been shown to have clinical value. In a review of our ATLL research findings, we have noticed the same trend in our search for an improved biomarker, and thus the discovery of a highly precise biomarker is one of the keys for the development of superior companion diagnostics.

Group I p21-activated kinases facilitate Tax-mediated transcriptional activation of the human T-cell leukemia virus type 1 long terminal repeats

BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and tropical spastic paraparesis. HTLV-1 encodes transactivator protein Tax that interacts with various cellular factors to modulate transcription and other biological functions. Additional cellular mediators of Tax-mediated transcriptional activation of HTLV-1 long terminal repeats (LTR) remain to be identified and characterized.ResultsIn this study, we investigated the regulatory role of group I p21-activated kinases (Paks) in Tax-induced LTR activation. Both wild-type and kinase-dead mutants of Pak3 were capable of potentiating the activity of Tax to activate LTR transcription. The effect of Paks on the LTR was attributed to the N-terminal regulatory domain and required the action of CREB, CREB-regulating transcriptional coactivators (CRTCs) and p300/CREB-binding protein. Paks physically associated with Tax and CRTCs. Paks were recruited to the LTR in the presence of Tax. siRNAs against either Pak1 or Pak3 prevented the interaction of Tax with CRTC1 and the recruitment of Tax to the LTR. These siRNAs also inhibited LTR-dependent transcription in HTLV-1-transformed MT4 cells and in cells transfected with an infectious clone of HTLV-1.ConclusionGroup I Paks augment Tax-mediated transcriptional activation of HTLV-1 LTR in a kinase-independent manner.

Abstract 2186: Quantitative cell surface proteome profiling of CD4+ T cells to identify potential therapeutic targets for adult T-cell leukemia (ATL).

Abstract Human T-cell leukemia virus type 1 (HTLV-1) is one of retroviruses known as the causative agent of adult T cell leukemia/lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), both of which develop after a long latency period over 30 years. ATL develops in HTLV-1-infected individuals at the prevalence of 5%, who exhibit only 20% overall 5-year survival rate. Recently, ATL treatment using Mogamulizumab showed 58 % of response rate in the clinical studies. However, adverse reactions were reported for all cases during the treatment. Moreover no effective treatment has been developed for the Mogamulizumab-resistant ATL patients. The objective of the present study is to discover molecular treatment targets for antibody therapies against ATL. For effective isolation of the therapeutic targets, comprehensive cell surface proteome profiling was performed. Since most of cell surface proteins are glycosylated, a glycopeptide enrichment technology IGEL (Isotopic Glycosidase Elution and labeling on Lectin column chromatography) was employed to focus on the cell surface proteins. The IGEL was previously developed in our group, which based on 96-well modified lectin column chromatography (Mol Cell Proteomics. 2010,9(9),1819). 1 × 106 of peripheral blood mononuclear cells (PBMCs) were lysed, reduced and alkylated followed by tryptic digestion. In this study, we used ConA lectin beads to enrich glycopeptides, which specifically recognized α-mannosyl or α-glucosyl residues of N-glycans. The eluates were lyophilized and subjected to LC/MS/MS analysis. The LC/MS/MS analysis identified 594 peptides derived from 268 proteins including 510 glycosylated peptides. Gene Ontology analysis revealed that 73.6% of identified proteins were assigned as the membrane associated proteins. For the therapeutic target screening experiment, CD4+ T cells were isolated from PBMCs derived from 16 uninfected volunteers, 25 asymptomatic carriers, 26 HAM/TSP patients, and 15 ATL patients. To perform relative quantification and subsequent statistical analysis of over 100,000 peptides among 82 samples, we employed the Expressionist proteome server system (Genedata AG). Although recent high-end mass spectrometers allow in-depth and comprehensive analysis of any proteomes, improvement of data processing infrastructures, such as Expressionist, should be essential for future clinical proteomics studies analyzing hundreds of specimens. Here we introduce a systematic workflow to identify ATL-specific cell surface antigens, accompanying further FACS-based replication experiments. In particular, our strategy could be useful for exploring any proteomic changes on cell surface, which include malignant transformation, metastasis, or cell development. Citation Format: Makoto Ishihara, Natsumi Araya, Tomoo Sato, Atae Utsunomiya, Yoshihisa Yamano, Yusuke Nakamura, Hidewaki Nakagawa, Koji Ueda. Quantitative cell surface proteome profiling of CD4+ T cells to identify potential therapeutic targets for adult T-cell leukemia (ATL). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2186. doi:10.1158/1538-7445.AM2013-2186

Tropical spastic paraparesis treated with Combivir (lamivudine–zidovudine)

Tropical spastic paraparesis (TSP) or human T-cell leukemia virus–type 1 (HTLV–I)-associated myelopathy is caused by human T-lymphotropic virus type 1. It is a slow, progressive spastic paraparesis with significant morbidity and causing profound repercussions on quality of life. No therapies have been found to persistently improve the outcome in these patients. We present a patient with HTLV–1-associated myelopathy/TSP (HAM/TSP) who was treated with Combivir® (lamivudine–zidovudine, GlaxoSmithKline, London, UK). She was walker-dependent for several years but, soon after treatment with lamivudine–zidovudine, was able to walk using only a cane. The role of lamivudine–zidovudine should be investigated further in this patient population.

Human T-lymphotropic Virus Type I (HTLV-I) Proviral Load and Clinical Features in Iranian HAM/TSP Patients: Comparison of HTLV-I Proviral Load in HAM/TSP Patients.

Human T-cell lymphotropic virus type I (HTLV-I) was the first human retrovirus discovered (1), and it has been estimated that 10-20 million people worldwide are infected with HTLV-I (2). This virus is endemic in several regions of the world, such as southwestern Japan, the Caribbean basin, Central Africa, South America, the Melanesian Islands, and the Middle East (3, 4). The prevalence of HTLV-I infection in Iran (Mashhad) is estimated to be 2-3% of the entire population, and 0.7% among blood donors (5). Most of HTLV-I-infected individuals remain asymptomatic carriers (6). Whereas, small percentage of infected individuals develop the neoplastic disease adult T-cell leukemia (ATL), and the inflammatory condition HTLV-I- associated myelopathy/tropical spastic paraparesis (HAM/TSP) (7). Only 5% of HTLV-I infected people develop HAM/TSP (8). HAM/TSP results in demyelination of the spinal cord and clinical manifestations of this disease include progressive muscle weakness and hyperreflexia of the lower limbs, sensory disturbance, urinary incontinence, and impotence (9-11). These symptoms are generally slowly progressive, while patients at older ages of onset show faster progression. Women are affected more frequently than men (12, 13). The precise pathophysiology of HAM/TSP is not yet clear but, previous studies suggested that both HTLV-I subgroups, host genetic and immunological factors may be associated with the development of HAM/TSP, particularly cytokine gene polymorphisms (14, 15). Proviral load is a major determinant of outcome for chronic virus infections such as HIV-1 and 2, hepatitis B virus, and hepatitis C virus. Also recent studies have suggested the important role of proviral load in the outcome of human T-lymphotropic virus-I infection (16). In patients with HAM/TSP, significantly higher proviral loads have been observed compared to asymptomatic carriers, suggesting that active HTLV-I viral replication plays a key role in the development of this disease. A recent study has shown that a high level of Tax expression and low CD8+ anti-viral efficiency are correlated with high proviral load (PVL) and HAM/TSP development (17). In a previous study the proviral load and host genetic risk factors for development of HAM/TSP between Iranian and Japanese HTLV-I infected individuals were compared, and it was found that the median HTLV-I proviral load of Iranian HAM/TSP patients was two-fold greater in HAM/TSP patients than in healthy carriers (HCs), whereas that of Japanese HAM/TSP patients was 13-fold greater than in HCs. In addition, The HTLV-I proviral load in Iranian HCs was significantly higher than Japanese HCs. These significant differences of proviral load between two populations reflect the role of genetic factors such as the human leukocyte antigen (HLA) genotype in populations. In this study the Iranian genome DNA samples were extracted from the whole blood but Japanese samples were from the peripheral blood mononuclear cells (PBMCs). The Iranian proviral load was probably underestimated in comparison with Japanese ones (18). The aim of this study was to evaluate the proviral load and clinical manifestation of HAM/TSP among Iranian to compare with other endemic parts of the world.

Association of IL-10 Gene Polymorphisms and Human T Lymphotropic Virus Type I-Associated Myelopathy/tropical Spastic Paraparesis in North-East of Iran (Mashhad).

The underlying mechanisms leading to the development of human T-cell lymphotropic virus type I (HTLV-I) associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-I infected individuals are not fully understood. Host genetic factors appear to be involved as risk factors for developing HAM/TSP. We investigated the possible contribution of interleukin-10 (IL-10) as a risk factor to HAM/TSP by comparing frequencies of promoter region single nucleotide polymorphisms in HTLV-I infected Iranian patients who either remained asymptomatic or developed HAM/TSP and asymptomatic HTLV-I carriers. Healthy, uninfected individuals from the same region served as healthy controls. Significant differences were observed in the distribution of IL-10 promoter alleles and genotypes at position -819 and -592 between HAM/TSP patients and healthy controls (P=0.01), and between HTLV-I carriers and healthy controls (P=0.02). The frequency of the low IL-10 producer haplotype (-1082*A, -819*T, -592*A) was significantly associated with HTLV-I carriage or HAM/TSP compared with healthy controls (P=0.02 and 0.01, respectively). Our results suggest that IL-10 -819*T and -592*A alleles are significant risk factors for developing HTLLV-I infection but do not appear to convey additional risk for developing HAM/TSP.

Effects of Danazol on Clinical Improvement of Patients with Human T-cell Lymphotropic Virus Type I Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP): A Placebo-Controlled Clinical Trial.

Human T-Cell Lymphotropic Virus Type I (HTLV-I) associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an endemic disease observed in Japan, Africa, Caribbean basin, and north-east Iran. It is usually presented as a chronic and progressive spastic paraparesis. There are some options for treatment of HAM/TSP patients. The aim of this study was to compare the effects of danazol controlled with placebo in relieving the symptoms and signs of HAM/TSP patients. Among 77 patients with definite diagnosis of HAM/TSP based on clinical and para-clinical findings, 71 patients had the required criteria for entering the study. Severity of symptoms and the degree of motor disability were determined before the beginning of treatment based on motor disability grading (MDG) in both groups of patients and were followed during 6 months in 1 month intervals for changes in symptoms and their motor disabilities. Among 38 patients of the first group, after 6 months therapy with danazol, mean difference between MDG0 (before starting the treatment) and MDG6 (after six months), as an indicator of motor improvement in the patients, was 0.89. Meanwhile, among the 33 patients treated with identical appearing placebo, there was no significant difference between MDG0 and MDG6 (P< 0.001). Moreover, there was a significant difference in improvement of symptoms between two study groups. This study showed that danazol provides relative effects on improving motor disabilities and symptoms of HAM/TSP patients that can be considered according to its lower side effects compared to other suggested treatments such as corticosteroids, and its lower costs in particular patients.

The Impact of Immune Response on HTLV-I in HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP).

Human T lymphotropic virus type I (HTLV-I) is a retrovirus which is associated with adult T cells leukaemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a minority of HTLV-I-infected individuals. It is not clear why a minority of HTLV-I-infected individuals develop HAM/TSP and majority remains lifelong carriers. It seems that the interaction between the virus and the immune response plays an important role in HTLV-I-associated diseases. Although the role of the immune response in HTLV-I pathogenesis is not fully understood, however it seems that the efficacy of the immune response which is involved in controlling or limiting of viral persistence determines the outcome of HTLV-I-associated diseases. Here we discuss the role of innate and adaptive immune response and also the risk factors contribute to the observed differences between HAM/TSP patients and asymptomatic HTLV-I carriers.

A Systematic Review for Estimation of HTLV-I Infection in the Blood Donors of Iran.

HTLV-I infection is a worldwide health problem and approximately 15–20 million persons are estimated to be infected with this infection (1). High HTLV-I seroprevalence rates in the general population or specific groups such as blood donors, have been reported from southwest of Japan, Caribbean basin, South America, Sub-Saharan Africa, and northeastern Iran (1,2). Although most infected people remain asymptomatic, the virus is associated with exceptionally severe diseases, such as adult T-cell leukemia/lymphoma (ATL), and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (3). HTLV-I infection could transmit from mother to child, predominantly through breastfeeding, via sexual intercourse, and parenteral transmission by transfusion of infected cellular blood products or sharing of needles and syringes (1,4). Presence of HTLV-I infection was reported in 1990 among the Jews emigrated from Mashhad, northeast of Iran (5), and then some patients with ATL were indentified in Mashhad who were seropositive for HTLV-I (6). In later studies, the rate of HTLV-I infection in Mashhad was reported 3% in general population (7) and about 2% in blood donors (8) in 1996. There were some small to large scale epidemiological studies that have reported the prevalence of HTLV-I infection in blood donors from various regions of the country. The widest survey has been conducted by Rezvan et al. in 21 regional blood centres in 1996. This study reported a 0.29% rate for HTLV-I infection in total serum samples; 1.97% among Mashhadi blood donors, and zero to 0.5 percent in other centres (8). Moreover, later surveys in several regions of Iran reported different rates of the infection in blood donors. Nevertheless, there is no overall estimation of the infection in the country. This study conducted to accurately estimate the prevalence of HTLV-I infection in the Iranian blood donors through a comprehensive systematic review of literature and evidences.

Population-based Seroprevalence of HTLV-I Infection in Golestan Province, South East of Caspian Sea, Iran.

Human T-cell lymphotropic virus type-1 is an oncornavirus that causes adult T cell leukemia (ATL) HTLV-I-associated myelopathy⁄tropical spastic paraparesis (HAM/TSP). Golestan province is located in North West of Khorasan province known as an endemic area for HTLV-I in Iran. This study aimed to evaluate seroprevalence of HTLV-I in Golestan province. In this cross-sectional descriptive study in 2007, blood samples were collected from 2034 healthy people residing in different parts of Golestan province. Sera were assessed for HTLV-I/II-specific antibodies by ELISA method and reactive samples were confirmed by Western blot. Demographic and serologic data were entered in SPSS version 11.5 and statistical analysis was performed. An overall HTLV-I/II prevalence of 0.7% was observed in 15 cases by ELISA. Six out of 15 were confirmed as HTLV-I by western blot. Regional variation in the prevalence of HTLV-I was observed; 0%, 0%, 0.1%, 1.9%, 0.3%, 0%, and 2.6% tested HTLV-I-positive from west to east of Golestan Province regions, respectively. Seropositivity increased with age. No association between HTLV-I infection and sex status was detected. Highest rate of HTLV-I seroprevalence was shown in east of this region located in neighborhood with Khorasan province, the only confirmed endemic area in Iran. It seems that eastern area of our province is endemic for HTLV-I. Further comprehensive detailed epidemiological and molecular studies are recommended.

"HTLV-I Infection" Twenty-Year Research in Neurology Department of Mashhad University of Medical Sciences.

Human T-cell lymphotropic virus (HTLV) types 1 and 2 belong to the Oncorna group of retroviridae, a large family of viruses, grouped initially by pathogenic features, but later revised on the basis of genome structure and nucleotide sequence. HTLV-I was the first discovered human retrovirus to be associated with a malignancy in 1980. The malignancy, first described by Uchiyama and co-workers in southwestern Japan, was named Adult T-cell Leukemia/Lymphoma (ATL) and characterized with cutaneous and respiratory involvement, hepatosplenomegaly, lymphadenopathy and various metabolic abnormalities such as hypercalcemia. The HTLV-I has been known to be endemic to certain parts of Iran like the province of Khorasan in the northeast since 1990, with a 2.3% prevalence rate of infection. The main manifestations of HTLV-I infection are neurologic and hematologic (such as ATL) disorders, but it has also other manifestations such as uveitis, arthritis, dermatitis, vitiligo and lymphocytic alveolitis. Its main neurologic manifestation is a chronic progressive myelopathy that is referred to HTLV-I Associated Myelopathy (HAM) in Japan and Tropical Spastic Paraparesis (TSP) in Caribbean. But other disorders such as peripheral neuropathy, polyradiculoneuropathy, myopathy, peripheral facial paresis, and so on have been reported too. In this review we wish to give some brief information on the different aspects (including epidemiology, pathogenesis and pathology, clinical findings, and treatment) of HTLV-I infection according to our twenty-year researches. The department of neurology of Mashhad University of Medical Sciences has been a pioneer in researches on HTLV-I in the last twenty years.