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Aims: HTLV-1 causes two life-threatening diseases: adult T-cell leukaemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis. Due to the lack of proper treatment, an effective HTLV-1 vaccine is urgently needed., Main Methods: DNA sequences of 11-19 and 178-186 amino acids of HTLV-1-Tax and SP2 and P21 were fused to the mouse-Fcγ2a, or His-tag called t Tax- t Env:mFcγ2a and t Tax- t Env:His, respectively. These constructs were produced in Pichia pastoris, and their immunogenicity and protective properties were assessed in a mouse challenging model with an HTLV-1-MT2 cell line., Key Findings: The immunogenicity assessments showed significant increase in IFN-γ production in animals receiving t Tax- t Env:mFcγ2a (1537.2 ± 292.83 pg/mL) compared to t Tax- t Env:His (120.28 ± 23.9, p = 0.02). IL-12 production also increased in group receiving t Tax- t Env:mFcγ2a than t Tax- t Env:His group, (23 ± 2.6 vs 1.5 ± 0.6, p = 0.01), respectively. The IFN-γ and IL-12 levels in the Fc-immunised group were negatively correlated with PVL (R = -0.82, p < 0.04) and (R = -0.87, p = 0.05), respectively. While, IL-4 was increased by t Tax- t Env:His (21.16 ± 1.76 pg/mL) compared to t Tax- t Env:mFcγ2a (13.7 ± 1.49, p = 0.019) with a negative significant correlation to PVL (R = -0.95, p = 0.001)., Significance: The mouse challenging assay with t Tax- t Env:mFcγ2a showed 50 % complete protection and a 50 % low level of HTLV-1-PVL compared to the positive control receiving HTLV-1-MT2 (p = 0.001). Challenging experiments for the His-tag protein showed the same outcome (p = 0.002) but by different mechanisms. The Fc-fusion construct induced more robust Th1, and His-tag protein shifted more to Th2 immune responses. Therefore, inducing both T helper responses, but a Th1/Th2 balance in favour of Th1 might be necessary for appropriate protection against HTLV-1 infection, spreading via cell-to-cell contact manner., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: NO authors have competing interests

Several studies suggest that HTLV-1 infection may be associated with a wider spectrum of neurologic manifestations that do not meet diagnostic criteria for HAM/TSP. These conditions may later progress to HAM/TSP or constitute an intermediate clinical form, between asymptomatic HTLV-1 carriers and those with full myelopathy. Our aim was to determine the prevalence of HTLV-1-associated disease in subjects without HAM/TSP, and the relationship between these findings with HTLV-1 proviral load (PVL)., Methods: 175 HTLV-1-infected subjects were submitted to a careful neurological evaluation, during their regular follow up at the HTLV outpatient clinic of the Institute of Infectious Diseases "Emilio Ribas", São Paulo city, Brazil. Clinical evaluation and blinded standardized neurological screening were performed for all the subjects by the same neurologist (MH)., Results: After the neurological evaluation, 133 patients were classified as asymptomatic and 42 fulfilled the criteria for intermediate syndrome (IS). The mean age of the enrolled subjects was 46.3 years and 130 (74.3%) were females. Clinical classification shows that neurological symptoms (p<0.001), visual disorders (p = 0.001), oral conditions (p = 0.001), skin lesions (p<0.001), bladder disorders (p<0.001), and rheumatological symptoms (p = 0.001), were strongly associated to IS, except for disautonomy (p = 0.21). A multivariate analysis revealed that HTLV-1 proviral load, oral conditions, bladder disorders and rheumatological symptoms were independently associated with the IS., Conclusions: We found some early alterations in 42 patients (24%), particularly the presence of previously not acknowledged clinical and neurological symptoms, among subjects previously classified as "asymptomatic", who we reclassified as having an intermediate syndrome., Competing Interests: No. The authors have declared that no competing interests exist.

The human T-lymphotropic virus type 1 (HTLV-1) is a RNA retrovirus that infects a minimum of 5-10 million people worldwide. Transmission by cell-containing blood products and solid organ transplantation has been reported. Clinical disease occurs in about 5-10% of infected individuals and consists mainly in adult T cell leukemia and HTLV-1-associated myelopathy (HAM). We present a 54-year-old woman who underwent kidney transplant from cadaveric donor in March 2015. Donor also underwent cornea extraction for another recipient (corneal transplant protocol includes HTLV-1/2 serology). Twenty-four hours after completion of kidney transplant donor, HTLV-1 serology was revealed positive. Following experts' recommendations, once donor seropositivity was demonstrated, antiviral prophylaxis including zidovudine and raltegravir was initially given to our patient, in spite of which the patient developed HAM. Once the diagnosis of HAM was established, antiretroviral therapy was restarted, and intravenous pulses of methylprednisolone were periodically administered with transient initial improvement. Later on, the patient experienced neurological deterioration becoming wheelchair dependent. Since the occurrence of this case, HTLV-1 screening has become mandatory for solid organ transplantation in the Spanish province of Navarra, and the same should happen worldwide.

The aim of this study was to compare computed tomography (CT) scans of chest and lung function among patients with Human T-Lymphotropic Virus Type 1 (HTLV) with and without HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). In this cross-sectional study performed between January 2013 and June 2016, we included 48 patients with HAM/TSP (19 women and 11 men) and without HAM/TSP (12 women and 6 men). We compared CT findings and lung functions of these groups. Patients who had HAM/TSP had abnormal CT findings (P = 0.000), including more frequent bronchiectasis (P = 0.049), parenchymal bands (P = 0.007), interlobular septal thickening (P = 0.035), and pleural thickening (P = 0.009). In addition, neither patients with HAM/TSP (9/30; 30%) nor the controls (0/18; 0%) had obstructive or restrictive lung disease (P = 0.009). HTLV diagnosis should be considered in all patients with abnormal CT findings in whom no other cause is apparent. It is important to remember that lung disease increases the rates of morbidity and mortality in developing countries.

Objectives: Human T-cell lymphotropic virus type 1 (HTLV-1) infection is associated with neurological abnormalities, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and peripheral neuropathy (PN). Hepatitis C virus (HCV) infection is the leading cause of chronic liver disease worldwide, and causes PN in approximately 9% of patients. Because the interplay between these potentially neuropathogenic viruses in the same individual is still poorly understood, the clinical and laboratory outcomes of co-infected patients were evaluated and compared with those of controls., Methods: The prevalence rates of neurological and laboratory abnormalities were evaluated in HCV/HTLV-1 co-infected patients (n=50), and in subjects with single HCV (n=46) or HTLV-1 (n=150) infection., Results: A higher frequency of isolated PN was present in HCV-infected patients; this was not associated with cryoglobulinemia. No difference was found in the frequency of PN or HAM/TSP when co-infected subjects were compared to singly infected subjects. Hepatic involvement was present in HCV-infected subjects, as shown by increased levels of serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and bilirubin, in addition to thrombocytopenia. On the other hand, HCV/HTLV-1 co-infected individuals presented a better prognosis for hepatic involvement when compared with singly HCV-infected subjects., Conclusions: These data suggest that HCV/HTLV-1 co-infection does not mutualistically alter the outcome with regard to neurological manifestations. Nonetheless, changes in the immunological environment induced by HTLV-1 infection could lead to a reduction in hepatic damage, even without significant HCV clearance., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Previous studies have suggested debatable roles of Tax and HBZ gene expression in the pathogenesis of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In this study, HTLV-1 and host interactions in the manifestation of HAM/TSP were evaluated., Methods: A cross-sectional study was conducted on 33 HAM/TSP patients and 38 HTLV-1 asymptomatic carriers (ACs). HTLV-1-Tax, HBZ gene expression, and proviral load (PVL) were assessed using the quantitative real-time PCR (TaqMan), host plasma neopterin level, and HLA-I, and the clinical manifestation were evaluated., Results: The HTLV-1 PVLs in HAM/TSP and ACs were 306±360.741 copies/10 4 PBMCs and 250.98±629.94 copies/10 4 PBMCs, respectively; the PVL was higher in HAM/TSP than that in ACs (p=0.004). HTLV-1 Tax and HBZ expression in HAM/TSP was higher than that in ACs, wherein only the Tax expression was statistically significant (p=0.039). In contrast to Japanese HTLV-1-infected subjects, HLA-A*02, HLA-A*24, HLA-Cw*08, and HLA-B*5401 did not exhibit preventive effects for HAM/TSP manifestation. The plasma neopterin level was significantly higher in HAM/TSPs than that in ACs; furthermore, there was a strong significant correlation between plasma neopterin and PVL (R=0.76, p=0.001). Moreover, there were significant correlation between urinary disturbances and haematological indices, including the RBC count (R=-0.61, p=0.01) and Hematocrit (Ht) index (R=-0.75, p=0.002), and between mobility disturbances with Tax expression (R=-0.58, p=0.02) and WBC counts (R=-0.54, p=0.04), and finally, a significant association was found between the sensory disturbances and PVL (p=0.05)., Conclusion: Overall, HTLV-1 PVL and Tax may be the valid predictors of disease development, and the neopterin level may be a valid predictor of disease progression. In addition, Tax and neopterin are more helpful than PVL for the monitoring of HTLV-1-infected patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

HTLV-1 infects principally CD4+ T cells that are the main reservoirs of the virus in vivo, which play an important role in the immunological response. Most of the infected patients are asymptomatic. However, 2-3% of patients will develop HAM/TSP or Adult T lymphoma. HAM/TSP is a chronic inflammatory disease of the central nervous system, which is characterized by unremitting myelopathic symptoms. Studies have shown that cytokines levels alterations (IFN-γ and TNF-α) were associated with tissue injury in HAM/TSP. The aims of this study were to compare the gene expression of IFN-γ, IL-4 and IL-10 of asymptomatic and HAM/TSP HTLV-1 infected patients, and to correlate the gene expression with those of clinical symptoms. 28 subjects were included, 20 asymptomatic HTLV-1 and 8 with HAM/TSP. Spasticity was evaluated using the Modified Ashworth Scale and the degree of walking aid was classified on a progressive scale. The relative gene expression of IFN-γ, IL-4, and IL-10 was measured by Real-Time PCR. Results showed high gene expression of IFN-γ for all patients, but it was higher among HAM/TSP. A significant correlation was observed between IFN-γ gene expression and the degree of walking aid, and IFN-γ gene expression was higher among wheelchair users compared to non-wheelchair users. No association was found with IL-4 and IL-10. These findings indicate that HAM/TSP patients express higher amounts of IFN-γ than asymptomatic patients, and more importantly, the expression of this cytokine was strongly correlated with the need of walking aid., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A small percentage of those infected with human T-lymphotropic virus type 1 (HTLV-1) develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a debilitating neurodegenerative disease. This disease impacts essential bodily functions, and since currently available treatments are considered to be poorly effective, there is a dire need to develop a truly effective treatment to suppress disease progression. Recently, the authors and others have determined that HTLV-1 in HAM/TSP patients primarily infects T cells expressing the chemokine receptor CCR4. The authors postulated that HTLV-1 causes these T cells to develop Th1-like functions that are critical for the pathogenesis of HAM/TSP. They described an inflammatory positive feedback loop in which cross-talk between these abnormal Th1-like cells and astrocytes produce and maintain spinal cord lesions in HAM/TSP patients. When an anti-CCR4 antibody was tested against cells from HAM/TSP patients, the antibody instigated the destruction of the CCR4-positive cells, reducing the number of infected cells and the amount of inflammatory activity. Thus, the anti-CCR4 antibody is expected to become a fundamentally new treatment for HAM/TSP that directly targets infected cells. The treatment is currently being tested in clinical trials.

Considering that there is no effective treatment for human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis, this study aimed to assess the impact of triple combination therapy-interferon-α, valproic acid, and prednisolone-on clinical outcomes, main HTLV-1 viral factors, and host anti-HTLV-1 antibody response. HTLV-1 proviral load (PVL), and HBZ and Tax mRNA expression levels were measured in peripheral blood mononuclear cells of 13 patients with HTLV-1-associated myelopathy/tropical spastic paraparesis before and after treatment with 180 μg pegylated interferon once a week, 10-20 mg/kg/day sodium valproate, and 5 mg/day prednisolone for 25 weeks using a TaqMan real-time polymerase chain reaction assay. Furthermore, anti-HTLV-1 titer, Osame Motor Disability Score, Ashworth spasticity scale, and urinary symptoms (through standard questionnaire and clinical monitoring) were assessed in patients before and after the treatment. HTLV-1 PVL and HBZ expression significantly decreased after the treatment [PVL from 1443 ± 282 to 660 ± 137 copies/10(4) peripheral blood mononuclear cells (p = 0.01); and HBZ from 8.0 ± 1.5 to 3.0 ± 0.66 (p < 0.01)]. Tax mRNA expression decreased after the treatment from 2.26 ± 0.45 to 1.44 ± 0.64, but this reduction was not statistically significant (p = 0.10). Furthermore, anti-HTLV-1 titer reduced dramatically after the treatment, from 3123 ± 395 to 815 ± 239 (p < 0.01). Clinical signs and symptoms, according to Osame Motor Disability Score and Ashworth score, improved significantly (both p < 0.01). Urinary symptoms and sensory disturbances with lower back pain were reduced, though not to a statistically significant degree. Although signs and symptoms of spasticity were improved, frequent urination and urinary incontinence were not significantly affected by the triple therapy. The results provide new insight into the complicated conditions underlying HTLV-1-associated diseases.

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease of the spinal cord, characterized by spastic paraparesis, back pain, and sphincter disorders. Involvement of multiple organs and encephalopathy are uncommon in HAM/TSP. Nonspecific small white matter lesions of unknown etiology, mainly in the periventricular and subcortical regions, have been found on brain magnetic resonance imaging of HAM/TSP patients. Bitemporal lesions have rarely been described. We report the case of a 54-year-old woman diagnosed with HAM/TSP who presented subclinical cognitive deficits associated with bitemporal and widespread white matter lesions. The cerebrospinal fluid (CSF) was inflammatory (blood-CSF barrier dysfunction, intrathecal synthesis of total and HTLV-1 IgG). The proviral load was higher in cerebrospinal fluid than in peripheral blood mononuclear cells. The neurological picture was complicated by multi-organ inflammatory disease (Hashimoto's thyroiditis, uveitis, anemia, and chronic renal failure). This case highlights the potential multisystem inflammatory nature of HTLV-1 infection, with a wide spectrum of manifestations. In cases of HAM/TSP with multi-organ inflammatory disease, encephalic involvement should be investigated, even in the absence of clinical manifestations. Also bitemporal lesions can be the consequence of intense and diffuse inflammation associated with HTLV-1 infection., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While risk factors for konzo are known, determinants of cognitive impairment in konzo-affected children remain unknown. We anchored cognitive performance (KABC-II scores) to serum levels of free-thyroxine (free-T4), thyroid-stimulating hormone (TSH), albumin, and motor proficiency (BOT-2 scores) in 40 children including 21 with konzo (median age: 9 years) and 19 without konzo (median age: 8 years). A multiple regression model was used to determine variables associated with changes in KABC-II scores. Age (β: -0.818, 95% CI: -1.48, -0.152) (p = 0.018), gender (β: -5.72; 95% CI: -9.87, -1.57 for females) (p = 0.009), BOT-2 score (β: 0.390; 95% CI: 0.113, 0.667) (p = 0.008), and free-T4 (β: 1.88; 95% CI: 0.009, 3.74) (p = 0.049) explained 61.1 % of variation in KABC-II scores. Subclinical hypothyroidism was not associated with poor cognition. A crude association was found between serum albumin and KABC-II scores (β: 1.26; 95 % CI: 0.136, 2.39) (p = 0.029). On spot urinary thiocyanate reached 688 μmol/l in children without konzo and 1,032 μmol/L in those with konzo. Female gender and low serum albumin are risk factors common to cognitive and proportionally associated motor deficits in children exposed to cassava cyanogens. The two types of deficits may share common mechanisms.

Recent studies have highlighted the importance of assessing the robustness of putative biomarkers identified from experimental data. This has given rise to the concept of stable biomarkers, which are ones that are consistently identified regardless of small perturbations to the data. Since stability is not by itself a useful objective, we present a number of strategies that combine assessments of stability and predictive performance in order to identify biomarkers that are both robust and diagnostically useful. Moreover, by wrapping these strategies around logistic regression classifiers regularized by the elastic net penalty, we are able to assess the effects of correlations between biomarkers upon their perceived stability. We use a synthetic example to illustrate the properties of our proposed strategies. In this example, we find that: (i) assessments of stability can help to reduce the number of false-positive biomarkers, although potentially at the cost of missing some true positives; (ii) combining assessments of stability with assessments of predictive performance can improve the true positive rate; and (iii) correlations between biomarkers can have adverse effects on their stability and hence must be carefully taken into account when undertaking biomarker discovery. We then apply our strategies in a proteomics context to identify a number of robust candidate biomarkers for the human disease HTLV1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in less than 5 % of HTLV-1 carriers. It is unclear which factors trigger the development of disease. The aim of this study was to explore the influence of HLA alleles on the development of HAM/TSP. A total of 40 HTLV-1-infected individuals belonging to the Spanish HTLV-1 cohort were examined. HTLV-1 proviral load was measured by real-time polymerase chain reaction. HLA class I (A, B, C) and class II (DRB1, DQB1) alleles were genotyped using the bead array technology. Median HTLV-1 proviral load in 12 HAM/TSP patients was greater than in 28 asymptomatic carriers (637 vs. 71 copies per 10(4) peripheral blood mononuclear cells; p = 0.006). Moreover, HAM/TSP was significantly associated with HLA-B 07 and HLA-DRB1 01:01 (p = 0.039). Interestingly, individuals with these HLA alleles had greater HTLV-1 proviral load than asymptomatic carriers (p = 0.036). In summary, HLA testing should be considered in asymptomatic HTLV-1 individuals and close monitoring of HTLV-1 proviral load along with periodic neurological evaluations should be prioritized in HLA-DRB1 01:01 and HLA-B 07 carriers.

Human T-cell leukemia virus type 1 (HTLV-1) causes both a neoplastic disease and inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 basic leucine zipper factor (HBZ) gene is encoded in the minus strand of the proviral DNA and is constitutively expressed in infected cells and ATL cells. HBZ increases the number of regulatory T (Treg) cells by inducing the Foxp3 gene transcription. Recent studies have revealed that some CD4⁺Foxp3⁺ T cells are not terminally differentiated but have a plasticity to convert to other T-cell subsets. Induced Treg (iTreg) cells tend to lose Foxp3 expression, and may acquire an effector phenotype accompanied by the production of inflammatory cytokines, such as interferon-γ (IFN-γ). In this study, we analyzed a pathogenic mechanism of chronic inflammation related with HTLV-1 infection via focusing on HBZ and Foxp3. Infiltration of lymphocytes was observed in the skin, lung and intestine of HBZ-Tg mice. As mechanisms, adhesion and migration of HBZ-expressing CD4⁺ T cells were enhanced in these mice. Foxp3⁻CD4⁺ T cells produced higher amounts of IFN-γ compared to those from non-Tg mice. Expression of Helios was reduced in Treg cells from HBZ-Tg mice and HAM/TSP patients, indicating that iTreg cells are predominant. Consistent with this finding, the conserved non-coding sequence 2 region of the Foxp3 gene was hypermethylated in Treg cells of HBZ-Tg mice, which is a characteristic of iTreg cells. Furthermore, Treg cells in the spleen of HBZ-transgenic mice tended to lose Foxp3 expression and produced an excessive amount of IFN-γ, while Foxp3 expression was stable in natural Treg cells of the thymus. HBZ enhances the generation of iTreg cells, which likely convert to Foxp3⁻T cells producing IFN-γ. The HBZ-mediated proinflammatory phenotype of CD4⁺ T cells is implicated in the pathogenesis of HTLV-1-associated inflammation.

Human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease characterized by chronic inflammation in the spinal cord. We hypothesized that a positive feedback loop driven by chemokines may be responsible for the chronic inflammation in HAM/TSP. We aimed to determine the identity of these chemokines, where they are produced, and how they drive chronic inflammation in HAM/TSP. We found that patients with HAM/TSP have extraordinarily high levels of the chemokine CXCL10 (also known as IP-10) and an abundance of cells expressing the CXCL10-binding receptor CXCR3 in the cerebrospinal fluid. Histological analysis revealed that astrocytes are the main producers of CXCL10 in the spinal cords of patients with HAM/TSP. Co-culture of human astrocytoma cells with CD4+ T cells from patients with HAM/TSP revealed that astrocytes produce CXCL10 in response to IFN-γ secreted by CD4+ T cells. Chemotaxis assays results suggest that CXCL10 induces migration of peripheral blood mononuclear cells to the central nervous system and that anti-CXCL10 neutralizing antibody can disrupt this migration. In short, we inferred that human T-lymphotropic virus type 1-infected cells in the central nervous system produce IFN-γ that induces astrocytes to secrete CXCL10, which recruits more infected cells to the area via CXCR3, constituting a T helper type 1-centric positive feedback loop that results in chronic inflammation.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease of the central nervous system caused by infection with human T-lymphotropic virus type-1 (HTLV-1). HAM/TSP is characterized by chronic inflammation in spinal cord, leading to neurodegeneration and consequently the patients with HAM/TSP suffer from unremitting myelopathic symptoms such as spastic paraparesis, lower limb sensory disturbance, and bladder/bowel dysfunction. In the past quarter century since the discovery of this disease, significant advances have been made in the field of HAM/TSP research. Here we summarize current clinical and pathophysiological knowledge on HAM/TSP and discusses future focus areas for research on this disease.

Human T-cell leukemia virus type 1 (HTLV-1) can cause an aggressive malignancy known as adult T-cell leukemia/lymphoma (ATLL) as well as inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Transgenic (Tg) mice expressing HTLV-1 Tax also develop T-cell leukemia/lymphoma and an inflammatory arthropathy that resembles rheumatoid arthritis. We found that 8 of 297 Tax-Tg mice developed HAM/TSP-like disease with symmetrical paraparesis of the hind limbs, but these symptoms were absent in non-Tg littermates and in other mice strains at our animal facilities. We could perform detailed evaluations for five of these mice. These evaluations showed that the disease was not inflammatory, unlike that in HAM/TSP patients, but instead involved the invasion of histiocytic sarcoma cells into the lumbar spinal cord from the bone marrow where they had undergone extensive proliferation.

Background: Renal transplantation (RTx) in carriers of human T-cell lymphotropic virus type 1 (HTLV-1) has a risk of developing overt leukemia upon immunosuppression. Although there have been a few reports of such cases, it is unclear HTLV-1 carrier if patients on the modern immunosuppressants would develop HTLV-1-associated myelopathy or adult T-cell leukemia lymphoma., Methods: We retrospectively reviewed the clinical outcomes of RTx in nine HTLV-1 carriers to assess a risk of developing leukemia from 2002 to 2011 using immunosuppression with a calcineurin inhibitor, mycophenolate mofetil (MMF), and steroid. The anti-CD25 monoclonal antibody basiliximab was used for induction. In two cases of ABO-incompatible RTx, the rituximab was also administered before RTx., Results: The ratio of male to female subjects was 2 to 7 with an overall mean recipient age of 54.3 ± 8.1 years. We prescribed cyclosporine (n = 5) or tacrolimus (n = 4). There was only one graft loss due to the death caused by aspiration pneumonia with a functioning graft. No one developed overt leukemia with combined treatment with MMF, basiliximab and rituximab., Conclusion: We concluded that RTx in HTLV-1 carriers could be performed using a modern immunosuppressive regimen, without the risk of developing leukemia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Human T-lymphotropic virus type 1 (HTLV-1) is known to cause HTLV-associated myelopathy (HAM)/tropical spastic paraparesis and adult T cell leukemia. A growing body of evidence links HTLV-1 infection with an increasing spectrum of disease, including uveitis, periodontal disease, arthropathy, sicca syndrome, and neurologic deficits., Objectives: Despite recent findings, the natural history of HTLV-1 infection remains poorly defined. This study was designed to better characterize initial clinical and neurological findings in individuals diagnosed with HTLV-1 infection., Study Design: We conducted a cross-sectional study of 71 individuals recently diagnosed with HTLV-1 and 71 uninfected age- and sex-matched blood donors in Salvador, Brazil. Subjects were administered a standardized questionnaire and underwent physical exam., Results: HTLV-1 infected subjects were significantly more likely than controls to report complaints of hand and foot numbness (OR=5.3; 95% CI: 1.8-15.3; p=0.002 and OR=4.0; 95% CI: 1.3-12; p=0.013 respectively), difficulty running (OR=4.0; 95% CI: 1.1-14.2; p=0.032), nocturia (OR=5.0; 95% CI: 1.1-22.8; p=0.038), arthralgia (OR=3.3; 95% CI: 1.4-7.7; p=0.006), and photophobia (OR=3.3; 95% CI: 1.4-7.7; p=0.006)., Conclusions: Neurologic, ocular and rheumatologic complaints may be the first manifestations of HTLV-1 infection. Therefore, all patients presenting with initial diagnosis should be rigorously screened for these symptoms., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Leprosy and human T cell lymphotropic virus type 1 infection are prevalent in Brazil. Coinfection by Mycobacterium leprae and HTLV-1 is reviewed and a case is reported. A 59 year-old woman was followed and HTLV-1 associated myelopathy was diagnosed during leprosy treatment. The clinical and neurological aspects of this unusual association were initially reviewed. Immunological markers and the possible prognoses due to the association of the diseases were discussed. The unexpected association of leprosy and HTLV-1 associated myelopathy may occur in endemic areas and causes difficulties in determining the correct diagnosis and adequate management of the neurological manifestations.

We report a 51-year-old man with human T lymphotropic virus type-1 (HTLV-1) associated myelopathy (HAM) manifested 10 months after renal transplantation. He had progressive spastic paralysis and neurogenic bladder for 10 years. HTLV-1 antibody are positive both serum and cerebral spinal fluid (CSF). Althoght HTLV-1 was not examined in the donor, it was suspected that the patient was infected by renal transplantation. After treatment of interferon-alpha (IFN-alpha), his motor function had improved and neopterin in CSF was decreased from 158 pmol/ml to 89 pmol/ml. This is a rare case of HAM after living renal transplantation. Cyclosporin and methylpredonisolone are used as immunosuppressants for preventing graft rejection. Time for developing HAM after renal transplantation was shorter than patients after cadaveric renal transplantation. More investigations are needed to clarify the mechanisms in the development of HAM associated with renal transplantation.

Throughout my research life, I experienced to discover the causes of some neurological diseases in Japan. 1) SMON (subacute myelo-optico-neuropathy). Since the early 1960s, a peculiar neurological disease became prevalent throughout Japan. Through the chemical analysis of the green urine, characteristic of this disease, it was found that this disease was caused by intoxication of the administered clioquinol, an anti-diarrheal drug. This discovery is a big topic in the history of Japanese medicine. 2) In early 1970s, I experienced many young patients with oedema and polyneuropathy in Kagoshima. Finally it was found that the disease was the long-forgotten beriberi, which had disappeared several decades ago. We must always be aware of beriberi even now, as far as we eat well-polished rice. 3) In 1972, we noticed a group of sporadic paraparesis in Kagoshima, which was 20 years later confirmed to be induced by human T lymphotropic virus type-I (HTLV-I). We named this disease as "HTLV-I associated myelopathy" (HAM). It gave a strong impact that the causative virus of adult T cell leukemia (ATL) can induce entirely different diseases, in terms of both the clinical course and the pathological features. It was also proven that HAM was identical with tropical spastic paraparesis, (TSP), which had been prevalent in many areas of tropical zones. These experiences are good examples of our slogan "to keep in mind to send message of scientific progress from the local area to the international stage.

Introduction: Konzo is a neuromyelopathy characterized by permanent spastic paraparesis, linked to a subacute poisoning by cyanide found in cassava. The purpose of the study is to describe the epidemiological aspects of konzo in health region No. 2 in the Central African Republic., Method: A descriptive cross-sectional study was conducted among patients collected during a one-month period (July 16 to August 16, 2007) of active surveillance for acute flaccid paralysis., Results: Eighty-one cases of konzo were identified during the study period, representing a prevalence of 10 per 100,000. Mean age of patients was 10.7+/-7.7 years. Children and women were most affected. The main warning signs were fatigability (97.6%), tremor (88.9%), walking difficulty (100.0%), dysarthria (67.9%) and a loss of visual acuity (65.4%). The predominant neurological signs were lower limb paresis (90.0%) and hyperesthesia (66.7%)., Conclusion: Konzo is a serious public health problem in this region of the Central African Republic. A prevention program should be set-up.

Despite abundant activated virus-specific cytotoxic T lymphocytes (CTLs), patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) showed a significantly higher frequency of infected T cells than did healthy virus carriers (HVCs). Here, we demonstrate that at a given proviral load, the frequency of CD8(+) T cells that are negative for specific costimulatory molecules was significantly higher in HAM/TSP than in age-matched HVCs and uninfected healthy controls (HCs), whereas the frequency of intracellular perforin-positive CD8(+) T cells was significantly lower in both HAM/TSP and HVCs than in HCs. An inverse correlation between HTLV-1 proviral load (PVL) and percent perforin-positive CD8(+) T cells were observed only in disease-protective allele HLA-A*02-positive HVCs, but not in HAM/TSP patients, whether HLA-A*02 positive or negative, nor in HLA-A*02-negative HVCs. Significantly lower perforin expression was observed in HTLV-1-specific than in cytomegalovirus-specific CD8(+) T cells. Majority of HTLV-1-specific CD8(+) T cells in HVCs showed a CD28(-)CD27(+) phenotype, whereas HAM/TSP showed a CD28(-)CD27(-) phenotype. HTLV-1-specific CD8(+) T cells from HAM/TSP patients showed significantly lower degranulation than HVCs by CD107a mobilization assay. These findings suggest that an impaired function of HTLV-1-specific CTLs is associated with failing antiviral control and disease HAM/TSP.

Background: CD4+CD25high regulatory T (TReg) cells modulate antigen-specific T cell responses, and can suppress anti-viral immunity. In HTLV-1 infection, a selective decrease in the function of TReg cell mediated HTLV-1-tax inhibition of FOXP3 expression has been described. The purpose of this study was to assess the frequency and phenotype of TReg cells in HTLV-1 asymptomatic carriers and in HTLV-1-associated neurological disease (HAM/TSP) patients, and to correlate with measures of T cell activation., Results: We were able to confirm that HTLV-I drives activation, spontaneous IFNgamma production, and proliferation of CD4+ T cells. We also observed a significantly lower proportion of CTLA-4+ TReg cells (CD4+CD25high T cells) in subjects with HAM/TSP patients compared to healthy controls. Ki-67 expression was negatively correlated to the frequency of CTLA-4+ TReg cells in HAM/TSP only, although Ki-67 expression was inversely correlated with the percentage of CD127low TReg cells in healthy control subjects. Finally, the proportion of CD127low TReg cells correlated inversely with HTLV-1 proviral load., Conclusion: Taken together, the results suggest that TReg cells may be subverted in HAM/TSP patients, which could explain the marked cellular activation, spontaneous cytokine production, and proliferation of CD4+ T cells, in particular those expressing the CD25highCD127low phenotype. TReg cells represent a potential target for therapeutic intervention for patients with HTLV-1-related neurological diseases.

This report describes a patient who developed human T-cell leukemia virus type I-associated myelopathy (HAM) following a living-donor liver transplantation (LDLT) for liver cirrhosis due to hepatitis C virus (HCV) infection. Both the recipient and the living donor (his sister) were human T-cell leukemia virus type I (HTLV-I) carriers. Since the LDLT, he had been treated with immunosuppressive drugs such as tacrolimus and steroids as well as interferon-alpha to prevent rejection and a recurrence of the HCV infection, respectively. Even though the HTLV-I proviral load had decreased upon interferon treatment, he developed a slowly progressive gait disturbance with urinary disturbance 2 years after the LDLT and was diagnosed with HAM. This appears to be the first report of HAM development in an HLTV-I-infected LDLT recipient.

Introduction: The human T cell lymphotropic virus type I (HTLV-I) is a retrovirus that causes tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM). Objectives. To describe neurological characteristics and the severity of disability in a sample of patients with TSP/HAM., Methods: All TSP/HAM patients consecutively admitted during 2006 at the Brasilia Sarah Hospital, neurology outpatient clinic were included in the study. HTLV-I infected patient fulfilled criteria for serological positivity at both ELISA and western blot. Ashworth spasticity scale, Barthel index of activities of daily living, kurtzke functional systems and the Expanded Disability Status Scale (EDSS) were applied. All patients performed electrophysiological studies (evoked potentials, electromyogram) and brain/spinal cord magnetic resonance imaging (MRI)., Results: Forty two of 249 paraparetic patients (16.9%; 26 females; mean age: 49.8 years) were diagnosed as having TSP/HAM. Mean time of evolution was 11.2 years. Most common neurological syndrome was a chronic progressive spastic paraparesis with hyperreflexia, ankle clonus and bilateral Babinski sign (97.7 %). Other findings were proximal muscle atrophy in lower limbs (28.6 %) , ataxia (21.4%), and peripheral neuropathy (7.1%). Half of patients were wheel-chair restricted or had a domiciliary walk. EDSS median was 6 and Barthel index mean score was 65. Most common findings on spinal cord MRI were thoracic spinal cord atrophy (66.7%) and white matter hyper-intensity areas in cerebral subcortical (42.8 %) and spinal cord (21.4%) regions., Conclusions: TSP/HAM is a very disabilitating disorder. Peripheral neuropathy and ataxia are other syndromes that should be included in the spectrum of HTLV-I infection.

Background: Dermatologic manifestations are quite common in patients with adult T cell leukemia and lymphoma and patients with myelopathy and/or tropical spastic paraparesis associated with human T cell lymphotropic virus type 1 (HTLV-1). The aim of this study was to investigate dermatological findings presented by 30 members of a Brazilian family, half of whom are infected with HTLV-1 (as confirmed by enzyme-linked immunosorbent assay and Western blot)., Methods: The subjects underwent dermatologic examination and laboratory assessment, which included the search for the HTLV-1 genome in peripheral blood mononuclear cells (PBMCs) by qualitative and semiquantitative polymerase chain reaction (PCR) and in skin samples by nested qualitative PCR and immunofluorescence assay., Results: We found that cases of xerotic dermatological alterations, including 3 cases of acquired ichthyosis, were more frequent among the infected patients (7 cases vs. none among the uninfected individuals; P=.0063). Other lesions observed in this group included impetigo, scabies, epidermal nevus, herpes zoster scar, rosacea, and juvenile acne. One HTLV-1-infected individual presented with concurrently acquired ichthyosis, impetigo, scabies, dermatophytosis, and seborrheic dermatitis. The PCR performed on PBMCs and skin samples from 24 patients confirmed the serological results in all cases. Additionally, the HTLV-1 proviral load was higher in patients with >1 skin lesion. Finally, HTLV-1 could be identified in the skin by immunofluorescence assay, which, by use of PCR as the gold standard, showed a sensitivity and specificity of 61.5% and 100%, respectively., Conclusions: Altogether, these clinical and laboratory findings point to an HTLV-1 tropism toward the skin, even in HTLV-1 carriers without adult T cell leukemia/lymphoma or HTLV-1-associated myelopathy and/or tropical spastic paraparesis.

Aggrecan, which is a well-known proteoglycan in joint cartilage, also exists in the spinal cord and plays an important role in maintaining water content in the extracellular matrix structure. In this study, we first examined the variable number of tandem repeat (VNTR) polymorphism of the aggrecan gene in 227 HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, in 217 HTLV-I-infected healthy carriers (HCs), and in 85 normal controls. The VNTR allele 28 (1,630 bp) was more frequently observed in HAM/TSP patients than in HCs (chi2=12.02, p=0.0005, odds ratio 1.79, 95% C.I. 1.29-2.50) and in controls (chi2=13.43, p=0.0002, odds ratio 2.54, 95% C.I. 1.52-4.25), although this allele was not related to disease progression or to HTLV-I provirus load. We also found that the aggrecan concentration in cerebrospinal fluid (CSF) from rapidly progressive HAM/TSP patients was significantly higher than in slowly progressive patients (corrected p=0.0145) but not in infected non-inflammatory neurological other disease controls (OND) (corrected p=0.078). We then analyzed this aggrecan VNTR polymorphism in the different set of patients with HAM/TSP (n=58) and healthy carriers (n=70). This analysis, again, revealed that allele 28 was detected more frequently in HAM/TSP group than in HCs (chi2=11.03, p=0.0009, odd ratio 3.04, 95% C.I. 1.55-5.97). The reproducibility of our study was regarded as a second- or third-class association by comparing combined p values and the Better Associations for Disease and GEnes (BADGE) system. Our results suggest that aggrecan polymorphism can be a novel genetic risk factor for developing HAM/TSP.

Objectives: We report the first two cases of HTLV-1 infection after a renal transplant appearing in our country and their outcomes., Methods: We describe the cases of two transplant patients who developed subacute myelopathy, known as Tropical Spastic Paraparesis, secondary to HTLV-1 infection and review their evolution., Results: Both cases show a great disability today, being one of them dependent for his daily life., Conclusions: We believe that HTLV-1 detection is necessary in all donors by indirect (ELISA) or direct (PCR) techniques due to its symptomless evolution in the transplant patient on the one hand, and the growing immigrant population in our country which associates an increase in the number of asymptomatic carriers of the virus.

Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus to be identified in the early 1980s. The isolation and identification of a related virus, HTLV-2, and the distantly related human immunodeficiency virus (HIV) immediately followed. Of the three retroviruses, two are associated definitively with specific diseases, HIV, with acquired immune deficiency syndrome (AIDS) and HTLV-1, with adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). While an estimated 10-20 million people worldwide are infected with HTLV-I, infection is endemic in the Caribbean, parts of Africa, southwestern Japan, and Italy. Approximately 4% of HTLV-I infected individuals develop ATLL, a disease with a poor prognosis. The clinical manifestations of infection and the current biology of HTLV viruses with emphasis on HTLV-1 are discussed in detail. The implications for improvements in diagnosis, treatment, intervention, and vaccination are included, as well as a discussion of the emergence of HTLV-1 and -2 as copathogens among HIV-1-infected individuals., (2005 Wiley-Liss, Inc.)

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is one outcome of human T-cell lymphotropic virus type-1 (HTLV-1) infection. It remains unknown why the majority of infected people remain healthy, whereas only approximately 2-3% of infected individuals develop the disease. The active form of vitamin D has immunomodulatory effects, and allelic variants of the vitamin D receptor (VDR) appear to be associated with differential susceptibility to several infectious diseases. To investigate whether VDR single nucleotide polymorphisms (SNPs) are associated with the development of HAM/TSP, we studied four VDR SNPs in a group of 207 HAM/TSP patients and 224 asymptomatic HTLV-1 seropositive carriers (HCs) in Kagoshima, Japan, by using PCR-RFLP analysis. We found that ApaI polymorphism of VDR is associated with the risk of HAM/TSP, although this polymorphism did not affect the provirus load of HTLV-1 in either HAM/TSP patients or HCs.

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disease observed only in 1-2 % of infected individuals. HTLV-1 provirus load, certain HLA alleles and HTLV-1 tax subgroups are reported to be associated with different levels of risk for HAM/TSP in Kagoshima, Japan. Here, it was determined whether these risk factors were also valid for HTLV-1-infected individuals in Mashhad in northeastern Iran, another region of endemic HTLV-1 infection. In Iranian HTLV-1-infected individuals (n=132, 58 HAM/TSP patients and 74 seropositive asymptomatic carriers), although HLA-DRB1*0101 was associated with disease susceptibility in the absence of HLA-A*02 (P=0.038; odds ratio=2.71) as observed in Kagoshima, HLA-A*02 and HLA-Cw*08 had no effect on either the risk of developing HAM/TSP or HTLV-1 provirus load. All Iranian subjects possessed tax subgroup A sequences, and the protective effects of HLA-A*02 were observed only in Kagoshima subjects with tax subgroup B but not in those with tax subgroup A. Both the prevalence of HTLV-1 subgroups and the host genetic background may explain the different risks levels for HAM/TSP development in these two populations.

As a model for molecular mimicry, we study patients infected with human T-lymphotropic virus type 1 (HTLV-1) who develop a neurological disease called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease with important biological similarities to multiple sclerosis (MS) (Khan et al. 2001; Levin et al. 1998, 2002a; Levin and Jacobson 1997). The study of HAM/TSP, a disease associated with a known environmental agent (HTLV-1), allows for the direct comparison of the infecting agent with host antigens. Neurological disease in HAM/TSP patients is associated with immune responses to HTLV-1-tax (a regulatory and immunodominant protein) and human histocompatibility leukocyte antigen (HLA) DRB1*0101 (Bangham 2000; Jacobson et al. 1990; Jeffery et al. 1999; Lal 1996). Recently, we showed that HAM/TSP patients make antibodies to heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), a neuron-specific autoantigen (Levin et al. 2002a). Monoclonal antibodies to tax cross-reacted with hnRNP A1, indicating molecular mimicry between the two proteins. Infusion of cross-reactive antibodies with an ex vivo system completely inhibited neuronal firing indicative of their pathogenic nature (Kalume et al. 2004; Levin et al. 2002a). These data demonstrate a clear link between chronic viral infection and autoimmune disease of the central nervous system (CNS) in humans and, we believe, in turn will give insight into the pathogenesis of MS.

Introduction: HTLV-I associated myelopathy is characterised by a clinical picture of slowly progressive spastic paraparesis that generally presents when the patient is at an age somewhere between his or her thirties and sixties; few cases have been reported involving children. It is a pathology that is prevalent in tropical regions that are endemic for HTLV-I (southern Japan, the Caribbean, Central and South America, and some areas of Africa)., Case Report: The authors report the case of a 9-year-old child from Guinea who was admitted to the Paediatric Neurology Unit in the Hospital de Santa Maria with a two-year-old clinical history of spastic paraparesis. Computerised tomography and magnetic resonance imaging did not show any alterations to the spinal cord. Somatosensory evoked potentials revealed a lesion in the posterior dorsolumbar spinal cord. The exclusion of other (infectious, metabolic and demyelinating) pathologies and the confirmation of infection by HTLV-I (by means of PCR) led to a diagnosis of myelopathy associated to this virus. Therapy was established with interferon alfa, but no appreciable significant improvement was observed., Discussion: This case stands out because of the uncommonness of this pathology at the paediatric age. We review the most relevant aspects of this disorder at the earliest ages, above all with regard to its epidemiology, transmission, clinical symptoms and complementary diagnostic examinations. Known therapeutic options (corticoids, interferon alfa, antiretroviral agents, among others) and prognosis are also discussed.

To investigate non-human leukocyte antigen candidate genes that influence the outcome of human T cell lymphotropic virus (HTLV) type I infection, we analyzed 6 single-nucleotide polymorphisms in the interleukin (IL)-10 promoter region in 280 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 255 HTLV-I-seropositive asymptomatic carriers from an area where HTLV-I is endemic. The IL-10 -592 A allele, which shows lower HTLV-I Tax-induced transcriptional activity than the C allele in the Jurkat T cell line, was associated with a >2-fold reduction in the odds of developing HAM/TSP (P=.011; odds ratio [OR], 0.50 [95% confidence interval, 0.30-0.86]) by reducing the provirus load in the whole cohort (P=.009, analysis of variance). Given the OR and the observed frequency of IL-10 -592 A, we demonstrate that this allele prevents approximately 44.7% (standard deviation, +/-13.1%) of potential cases of HAM/TSP, which indicates that it defines one component of the genetic susceptibility to HAM/TSP in the cohort.

The cerebrospinal fluid (CSF) is in direct contact with the extracellular space of the CNS, thus biochemical processes in the CNS could potentially be reflected in the CSF. Changes in extracellular matrix (ECM) proteins can be studied through their analysis in the CSF. ECM plays an essential role in CNS homeostasis and several proteins such as laminin (LN), fibronectin (FN), thrombospondin (TS) and heparan sulphate proteoglycan (HS, perlecan) form part of its structure. Possible changes in the levels of these proteins were investigated in two different pathologies--tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) (n=25) and Creutzfeldt-Jakob disease (CJD) (n=19)--and compared with those in a control group with or without neurological disease (n=25). CSF analyses were carried out using monoclonal or monospecific polyclonal antibodies. In comparison with the control group, it was found that TSP/HAM patients presented significantly higher levels of LN, TS and HS, while in CJD patients the levels of FN, TS and HS were increased. In CJD patients the HS level was almost double that of the TSP/HAM patients. These results suggest a distinct pattern of ECM proteins in CSF in relation to the type of neurological disease. TSP/HAM is a chronic motor disease that affects the white matter of the spinal cord, while CJD is a subacute dementia that affects cerebral neurons and their synapsis.

The epidemiology of tropical spastic paraparesis/human T lymphotropic virus I (HTLV-I)-associated myelopathy (TSP/HAM) is frequently inconsistent and suggests environmental factors in the etiology of these syndromes. The neuropathology corresponds to a toxometabolic or autoimmune process and possibly not to a viral disease. Some logical hypotheses about the etiology and physiopathology of TSP and HAM are proposed. Glutamate-mediated excitotoxicity, central distal axonopathies, cassava, lathyrism and cycad toxicity may explain most cases of TSP. The damage caused to astrocytes and to the blood-brain barrier by HTLV-I plus xenobiotics may explain most cases of HAM. Analysis of the HTLV-I/xenobiotic ratio clarifies most of the paradoxical epidemiology of TSP and HAM. Modern neurotoxicology, neuroimmunology and molecular biology may explain the neuropathology of TSP and HAM. It is quite possible that there are other xenobiotics implicated in the etiology of some TSP/HAMs. The prevention of these syndromes appears to be possible today.

Human T-lymphotropic virus type 1 (HTLV-1) varies little in sequence compared with human immunodeficiency virus type 1 (HIV) and it is difficult to detect HTLV-1 mRNA, proteins or virions in fresh blood. But the strong and chronically activated T cell response to the virus indicates that HTLV-1 proteins are expressed persistently. It now appears that the efficiency of an individual's cytotoxic T cell (CTL) response to HTLV-1 is the chief single determinant of that person's provirus load, which can differ between HTLV-1-infected people by more than 10 000-fold. Progress is now being made towards defining this CTL 'efficiency' in terms of host genetics, T cell function, T cell gene expression and mathematical dynamics. Lymphocytes that are naturally infected with HTLV-1 do not produce enveloped extracellular virions in short-term culture and this has reinforced the erroneous conclusion that the virus is latent. But recent evidence shows that HTLV-1 can spread directly between lymphocytes across a specialized, virus-induced cell-cell contact - a 'viral synapse'. Instead of making extracellular virions, HTLV-1 uses the mobility of the host cell to spread within and between hosts. In this review the evidence is summarized on the persistent gene expression of HTLV-1 in vivo, the role of the immune system in protection and pathogenesis in HTLV-1 infection, and the mechanism of cell-to-cell spread of HTLV-1.

Significantly higher frequencies of tumor necrosis factor alpha- and interleukin-2-secreting human T-lymphotropic virus type 1 (HTLV-1)-specific CD4(+) T cells were present in the peripheral blood mononuclear cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients than in those of asymptomatic carriers with similar provirus loads. The data suggest that HTLV-1-specific CD4(+) T cells play a role in the pathogenesis of HAM/TSP.

Background: The human T-cell lymphotrophic virus (HTLV) causes adult T-cell leukemia-lymphoma, tropical spastic paraparesis-HTLV type I, and associated myelopathy., Methods: An analysis was performed of serum samples from a multiorgan donor and the five recipients. Also studied was the donor's family and the partner of one of the renal recipients. Serologic detection of anti-HTLV antibodies was carried out by enzyme immunoassay and Western blot to confirm and discriminate between HTLV types. Analysis of proviral DNA was performed by polymerase chain reaction and sequenced in the long terminal repeat region and the env gene. Peripheral blood mononuclear cell samples from all the recipients of the HTLV-I-positive organs and the donor's mother were studied., Results: Two years after transplantation, three organ recipients positive for antibodies to HTLV-I were detected (two kidney transplants and one liver). All the recipients' serum samples were negative at the time of transplantation except those from the multiorgan donor. The donor's mother was born in Venezuela and was confirmed positive for antibodies to HTLV-I. The remaining family members were negative. HTLV-I DNA sequences were recovered, amplified, and sequenced from all the samples from the HTLV-I-positive recipients and the donor's mother. The homology of HTLV-I sequences was 100% in all cases., Conclusions: The authors are reporting the first documented case of HTLV-I infection in several transplant recipients sharing the same donor. The donor was infected by vertical transmission. HTLV-I infection has devastating consequences for some immunocompromised organ recipients. This emphasizes the need for a systematic survey of HTLV antibodies in all potential donors.