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1.  Leukotrienes Are Upregulated and Associated with Human T-Lymphotropic Virus Type 1 (HTLV-1)-Associated Neuroinflammatory Disease 
PLoS ONE  2012;7(12):e51873.
Leukotrienes (LTs) are lipid mediators involved in several inflammatory disorders. We investigated the LT pathway in human T-lymphotropic virus type 1 (HTLV-1) infection by evaluating LT levels in HTLV-1-infected patients classified according to the clinical status as asymptomatic carriers (HACs) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients. Bioactive LTB4 and CysLTs were both increased in the plasma and in the supernatant of peripheral blood mononuclear cell cultures of HTLV-1-infected when compared to non-infected. Interestingly, CysLT concentrations were increased in HAM/TSP patients. Also, the concentration of plasma LTB4 and LTC4 positively correlated with the HTLV-1 proviral load in HTLV-1-infected individuals. The gene expression levels of LT receptors were differentially modulated in CD4+ and CD8+ T cells of HTLV-1-infected patients. Analysis of the overall plasma signature of immune mediators demonstrated that LT and chemokine amounts were elevated during HTLV-1 infection. Importantly, in addition to CysLTs, IP-10 was also identified as a biomarker for HAM/TSP activity. These data suggest that LTs are likely to be associated with HTLV-1 infection and HAM/TSP development, suggesting their putative use for clinical monitoring.
PMCID: PMC3527467  PMID: 23284797
2.  Immunological and Viral Features in Patients with Overactive Bladder Associated with Human T-Cell Lymphotropic Virus Type 1 Infection 
Journal of medical virology  2012;84(11):1809-1817.
The majority of patients infected with human T-cell lymphotropic virus-type 1 (HTLV-1) are considered carriers, but a high frequency of urinary symptoms of overactive bladder, common in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) have been documented in these patients. The aim of this study was to determine if immunological and viral factors that are seen in HAM/TSP are also observed in these patients. Participants were classified as HTLV-1 carriers (n=45), HTLV-1 patients suffering from overactive bladder (n=45) and HAM/TSP (n=45). Cells from HTLV-1 overactive bladder patients produced spontaneously more proinflammatory cytokines than carriers. TNF-α and IL-17 levels were similar in HAM/TSP and HTLV-1 overactive bladder patients. High proviral load was found in patients with overactive bladder and HAM/TSP and correlated with proinflammatory cytokines. In contrast with findings in patients with HAM/TSP, serum levels of Th1 chemokines were similar in HTLV-1 overactive bladder and carriers. Exogenous addition of regulatory cytokines decreased spontaneous IFN-γ production in cell cultures from HTLV-1 overactive bladder patients. The results show that HTLV-1 overactive bladder and HAM/TSP patients have in common some immunological features as well as similar proviral load profile. The data show that HTLV-1 overactive bladder patients are still able to down regulate their inflammatory immune response. In addition, these patients express levels of chemokines similar to carriers, which may explain why they have yet to develop the same degree of spinal cord damage as seen in patients with HAM/TSP. These patients present symptoms of overactive bladder, which may be an early sign of HAM/TSP.
PMCID: PMC3457650  PMID: 22997085
HTLV-1; immune response; cytokines; chemokines; proviral load
3.  Bronchoalveolar lymphocytosis correlates with human T lymphotropic virus type I (HTLV-I) proviral DNA load in HTLV-I carriers 
Thorax  2005;60(2):138-143.
Background: A study was undertaken to investigate the pathogenesis of pulmonary involvement in human T lymphotropic virus type I (HTLV-I) carriers.
Methods: The bronchoalveolar lavage (BAL) cell profile of 30 HTLV-I carriers (15 asymptomatic HTLV-I carriers (AHCs) and 15 symptomatic HTLV-I carriers (SHCs)) with chronic inflammatory diseases of respiratory tract and eight patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) was investigated. The HTLV-I proviral deoxyribonucleic acid (DNA) load in peripheral blood mononuclear cells (PBMCs) and BAL fluid from HTLV-I carriers was estimated using the quantitative polymerase chain reaction method and the correlation between the lymphocyte number in BAL fluid and the HTLV-I proviral DNA load in PBMCs and BAL fluid was examined.
Results: The percentage of lymphocytes in BAL fluid was increased (>18%) in 11 of 30 HTLV-I carriers although there was no significant difference compared with control subjects. In HTLV-I carriers the lymphocyte number in BAL fluid correlated well with the copy number of HTLV-I proviral DNA in PBMCs. In addition, the copy number of HTLV-I proviral DNA in BAL fluid correlated well with the number of lymphocytes (both CD4+ and CD8+ cells) in BAL fluid.
Conclusions: These findings suggest that pulmonary lymphocytosis can occur in a subset of HTLV-I carriers without HAM/TSP and that the increased HTLV-I proviral DNA load may be implicated in the pathogenesis of pulmonary involvement in HTLV-I carriers.
PMCID: PMC1747290  PMID: 15681503
4.  Genetic control and dynamics of the cellular immune response to the human T-cell leukaemia virus, HTLV-I. 
About 1% of people infected with the human T-cell leukaemia virus, type 1 (HTLV-I) develop a disabling chronic inflammatory disease of the central nervous system known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have a vigorous immune response to HTLV-I, and it has been widely suggested that this immune response, particularly the HTLV-I-specific cytotoxic T-lymphocyte (CTL) response, causes the tissue damage that is seen in HAM/TSP. In this paper we summarize recent evidence that a strong CTL response to HTLV-I does in fact protect against HAM/TSP by reducing the proviral load of HTLV-I. We conclude that HTLV-I is persistently replicating at a high level, despite the relative constancy of its genome sequence. These results imply that antiretroviral drugs could reduce the risk of HAM/TSP by reducing the viral load, and that an effective anti-HTLV-I vaccine should elicit a strong CTL response to the virus. The dynamic nature of the infection also has implications for the epidemiology and the evolution of HTLV-I.
PMCID: PMC1692558  PMID: 10365395
5.  High HTLV-1 proviral load, a marker for HTLV-1-associated myelopathy/tropical spastic paraparesis, is also detected in patients with infective dermatitis associated with HTLV-1 
Salvador (BA, Brazil) is an endemic area for human T-cell lymphotrophic virus type 1 (HTLV-1). The overall prevalence of HTLV-1 infection in the general population has been estimated to be 1.76%. HTLV-1 carriers may develop a variety of diseases such as adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and infective dermatitis associated with HTLV-1 (IDH). IDH is a chronic and severe form of childhood exudative and infective dermatitis involving mainly the scalp, neck and ears. It has recently been observed that 30% of patients with IDH develop juvenile HAM/TSP. The replication of HTLV-1 has been reported to be greater in adult HAM/TSP patients than in asymptomatic HTLV-1 carriers. In the current study, the proviral load of 28 children and adolescents with IDH not associated with HAM/TSP was determined and the results were compared to those obtained in 28 HTLV-1 adult carriers and 28 adult patients with HAM/TSP. The proviral load in IDH patients was similar to that of patients with HAM/TSP and much higher than that found in HTLV-1 carriers. The high levels of proviral load in IDH patients were not associated with age, duration of illness, duration of breast-feeding, or activity status of the skin disease. Since proviral load is associated with neurological disability, these data support the view that IDH patients are at high risk of developing HAM/TSP.
PMCID: PMC2963476  PMID: 19578703
Infective dermatitis associated with HTLV-1; HTLV-1-associated myelopathy/tropical spastic paraparesis; HTLV-1 proviral loads
6.  Neuropsychological assessment in HTLV-1 infection: a comparative study among TSP/HAM, asymptomatic carriers, and healthy controls 
Background: Human T cell lymphotropic virus type 1 (HTLV-I) can cause tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) and adult T cell leukaemia/lymphoma. More recently other diseases such as isolated peripheral polyneuropathy, myopathy, artropathy, and uveitis have been associated with this retrovirus. Only a few uncontrolled studies, without necessary exclusion criteria, have described mild cognitive deficits among TSP/HAM patients. To further clarify this the authors evaluated, through neuropsychological testing patients with TSP/HAM and asymptomatic infected carriers, comparing both groups with healthy controls.
Objectives: To verify the presence of cognitive deficits among TSP/HAM patients and asymptomatic HTLV-1 infected carriers. In addition, the authors aimed to investigate if these deficits correlated with the degree of motor impairment in TSP/HAM patients.
Methods: From a cohort of 501 HTLV-1 infected people the authors selected, according to predefined inclusion and exclusion criteria, 40 asymptomatic HTLV-1 carriers and 37 TSP/HAM patients. Neuropsychological testing was blindly performed in both groups and their scores were compared with those obtained from controls.
Results: Both the HTLV-1 carrier group and the group of patients with TSP/HAM exhibited a lower performance in neuropsychological tests when compared with controls. Asymptomatic infected carriers and TSP/HAM patients did not differ in their cognitive results. Also, there was no relation between the degree of motor disability and cognitive deficits in the TSP/HAM group. Psychomotor slowing and deficits in the some domains characterised the neuropsychological impairment in HTLV-1 infection: verbal and visual memory, attention and visuomotor abilities.
Conclusions: TSP/HAM as well as asymptomatic infection can be associated with mild cognitive deficits. This finding, if confirmed by further studies, will permit the inclusion of cognitive impairment among the neurological manifestations of HTLV-1.
PMCID: PMC1738599  PMID: 12876239
7.  PCR-in situ hybridization detection of human T-cell lymphotropic virus type 1 (HTLV-1) tax proviral DNA in peripheral blood lymphocytes of patients with HTLV-1-associated neurologic disease. 
Journal of Virology  1996;70(2):924-933.
PCR-in situ hybridization (PCR-ISH) was developed and utilized to determine the distribution of human T-cell lymphotropic virus type 1 (HTLV-1) tax proviral DNA in peripheral blood lymphocytes (PBL) from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). PCR-ISH of HTLV-1 tax DNA in PBL from patients with HAM/TSP revealed that 1 in 5,000 to 1 in 10,000 PBL contained virus. PCR-ISH was sensitive, because a positive signal was consistently demonstrated from the HTLV-1-infected cell lines HUT-102 (which contains four to six copies of HTLV-1 proviral DNA per cell) and MT-1 (which contains one to three copies of HTLV-1 proviral DNA per cell). Also, intracellular amplification by PCR-ISH significantly increased sensitivity compared with conventional ISH and was shown to be specific for HTLV-1 tax DNA. These results are in contrast to solution-phase PCR amplification in which greater than 1% of cells were estimated to be infected. The discordance between these results is discussed and may indicate that more than one copy of HTLV-1 tax proviral DNA is present in an individual PBL.
PMCID: PMC189896  PMID: 8551632
8.  Brain Magnetic Resonance Imaging White Matter Lesions Are Frequent in HTLV-I Carriers and Do Not Discriminate from HAM/TSP 
AIDS research and human retroviruses  2007;23(12):1499-1504.
Human T lymphotropic virus (HTLV)-I is known to cause HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other pronounced disease in less than 4% of those infected. However, evidence is accumulating that a proportion of HTLV-I carriers have neurological and urological symptoms without fulfilling criteria for HAM/TSP. Brain white matter (WM) lesions on magnetic resonance imaging (MRI) are frequently seen in HAM/TSP. HTLV-I carriers with MRI scans for other neurological diagnoses have WM lesions more frequently than expected. We studied 10 patients with HAM/TSP and 20 HTLV-I carriers without overt neurological disease and evaluated clinical characteristics, viral load, total, small, large, confluent WM lesion number, and lesion volume on MRI. Cerebral WM lesions were found in of 85% of HTLV-I carriers and 80% of HAM/TSP patients. Lesion number, size or location was no different between carriers and HAM/TSP. Cognitive function was lower in HAM/TSP (p = 0.045) but did not correlate with WM lesion number. Viral load and peripheral blood mononuclear cell interferon-γ production correlated positively (p = 0.001) but did not correlate with lesion number or volume. Conventional brain MRI frequently shows WM lesions in HTLV-I-infected individuals suggesting potential early central nervous system inflammation with rare development of progressive disease.
PMCID: PMC2593463  PMID: 18160007
9.  Increased number of circulating HTLV-1 infected cells in peripheral blood mononuclear cells of HTLV-1 uveitis patients: a quantitative polymerase chain reaction study. 
AIMS--This study aimed to characterise the status of viral infection in patients with HTLV-1 uveitis (HU) by quantifying the circulating HTLV-1 infected cells in the peripheral blood. METHODS--Genomic DNA samples of peripheral blood mononuclear cells (PBMC) were obtained from 25 patients with HU, 14 patients with tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM), and 21 asymptomatic carriers of HTLV-1. Quantitative polymerase chain reaction (PCR) of the gag region of HTLV-1 provirus DNA was performed on these DNA samples. To confirm the PCR, genomic Southern blot hybridisation was performed to identify integrated HTLV-1 provirus. This procedure detected a few percent of HTLV-1 infected cells in the PBMC. RESULTS--Most of the HU patients had a significantly increased number of circulating HTLV-1 infected cells (mean (SD) 3.84% (4.45%) of the PBMC), whereas the percentage of infected cells in most asymptomatic carriers was less than 1% (0.54% (1.11%)). Most of the TSP/HAM patients also had a relatively high percentage (11.63% (7.67%)). The differences among these three groups were highly significant by the Mann-Whitney U test. CONCLUSION--The results suggested that the increase in the number of HTLV-1 infected cells is one base for the development of inflammatory HU lesions, as it is for TSP/HAM.
PMCID: PMC505078  PMID: 7703209
10.  Systems Biology Approaches Reveal a Specific Interferon-Inducible Signature in HTLV-1 Associated Myelopathy 
PLoS Pathogens  2012;8(1):e1002480.
Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that persists lifelong in the host. In ∼4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. We used gene expression microarrays followed by flow cytometric and functional assays to investigate global changes in blood transcriptional profiles of HTLV-1-infected and seronegative individuals. We found that perturbations of the p53 signaling pathway were a hallmark of HTLV-1 infection. In contrast, a subset of interferon (IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. We conclude that over-expression of a subset of IFN-stimulated genes in chronic HTLV-1 infection does not constitute an efficient host response but instead contributes to the development of HAM/TSP.
Author Summary
Infection with the Human T Lymphotropic virus is widespread in the tropics and subtropics, where it causes a chronic disabling disease of the nervous system abbreviated as HAM/TSP. There is no effective treatment available for HAM/TSP, because it is not understood how the virus causes the neuronal damage that results in the clinical symptoms of weakness and paralysis of the legs. Here, we compared the frequencies of cell populations and gene expression profiles from diseased and asymptomatic HTLV-1 carriers to identify abnormalities in biological pathways that cause HAM/TSP. We discovered a distinct group of genes that is over-expressed in white blood cells in patients with HAM/TSP, but not asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The expression of these genes is induced by interferons, a group of anti-viral proteins that are usually beneficial to the host but can also cause inflammation. We also found that interferons did not efficiently suppress HTLV-1 protein expression in vitro. We conclude that interferons do not control chronic HTLV-1 infection but instead contribute to the development of HAM/TSP. Our study provides new insights into the development of HTLV-1-associated diseases and opens new areas of therapeutic intervention.
PMCID: PMC3266939  PMID: 22291590
11.  Anti-HTLV antibody profiling reveals an antibody signature for HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) 
Retrovirology  2008;5:96.
HTLV-I is the causal agent of adult T cell leukemia (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Biomarkers are needed to diagnose and/or predict patients who are at risk for HAM/TSP or ATLL. Therefore, we investigated using luciferase immunoprecipitation technology (LIPS) antibody responses to seven HTLV-I proteins in non-infected controls, asymptomatic HTLV-I-carriers, ATLL and HAM/TSP sera samples. Antibody profiles were correlated with viral load and examined in longitudinal samples.
Anti-GAG antibody titers detected by LIPS differentiated HTLV-infected subjects from uninfected controls with 100% sensitivity and 100% specificity, but did not differ between HTLV-I infected subgroups. However, anti-Env antibody titers were over 4-fold higher in HAM/TSP compared to both asymptomatic HTLV-I (P < 0.0001) and ATLL patients (P < 0.0005). Anti-Env antibody titers above 100,000 LU had 75% positive predictive value and 79% negative predictive value for identifying the HAM/TSP sub-type. Anti-Tax antibody titers were also higher (P < 0.0005) in the HAM/TSP compared to the asymptomatic HTLV-I carriers. Proviral load correlated with anti-Env antibodies in asymptomatic carriers (R = 0.76), but not in HAM/TSP.
These studies indicate that anti-HTLV-I antibody responses detected by LIPS are useful for diagnosis and suggest that elevated anti-Env antibodies are a common feature found in HAM/TSP patients.
PMCID: PMC2580768  PMID: 18937847
12.  Molecular characterization of HTLV-1 gp46 glycoprotein from health carriers and HAM/TSP infected individuals 
Virology Journal  2013;10:75.
Human T-cell Leukemia Virus type 1 (HTLV-1) is the etiological agent of tropical spastic paraparesis/HTLV-associated myelopathy (HAM/TSP) that can be identified in around 0.25%–3.8% of the infected population. Disease progression can be monitored by the proviral load and may depend on genetic factors, however, it is not well understood why some HTLV-1 infected people develop the disease while others do not. The present study attempts to assess the molecular diversity of gp46 glycoprotein in HAM/TSP patients and Health Carrier (HC) individuals.
Blood samples were collected from 10 individuals, and DNA was extracted from PBMCs to measure the HTLV-1 proviral load. The gp46 coding sequences were amplified PCR, cloned and sequenced. The molecular characterization was performed using bioinformatics tools.
The median HTLV-1 proviral load of HC (n = 5) and HAM/TSP (n = 5) patients was similar (average 316,227 copies/106 PBMCs). The gp46 molecular characterization of 146 clones (70 HC and 76 HAM/TSP) revealed an overall diversity, within HC and HAM/TSP clones, of 0.4% and 0.6%, respectively. Five frequent mutations were detected among groups (HAM/TSP and HC clone sequences). A single amino acid (aa) substitution (S35L) was exclusive for the HC group, and three gp46 substitutions (F14S, N42H, G72S) were exclusive for the HAM/TSP group. The remaining frequent mutation (V247I) was present in both groups (p = 0.0014). The in silico protein analysis revealed that the mutated alleles F14S and N42H represent more hydrophilic and flexible protein domains that are likely to be less antigenic. The Receptor Binding Domain is quite variable in the HAM/TSP group. Two other domains (aa 53–75 and 175–209) that contain multiple linear T-cell epitopes showed genetic diversity in both HAM/TSP and HC groups. Further analysis revealed 27 and 13 T-cell epitopes for class I HLA alleles and class II HLA alleles, when analyzing the entire gp46.
The most common gp46 mutations were not associated clinical status because they were found in only one individual, except for the V247I mutation, that was found at viral clones from HAM/TSP ad HC individuals. Because of this, we cannot associate any of the gp46 found mutations with the clinical profile.
PMCID: PMC3599561  PMID: 23510700
HTLV-1; HAM/TSP; Gp46; Mutation
13.  Humoral immune response to HTLV-1 basic leucine zipper factor (HBZ) in HTLV-1-infected individuals 
Retrovirology  2013;10:19.
Human T cell lymphotropic virus type 1 (HTLV-1) infection can lead to development of adult T cell leukemia/lymphoma (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. HTLV-1 basic leucine zipper factor (HBZ) gene has a critical role in HTLV-1 infectivity and the development of ATL and HAM/TSP. However, little is known about the immune response against HBZ in HTLV-1-infected individuals. In this study, we examined antibody responses against HBZ in serum/plasma samples from 436 subjects including HTLV-1 seronegative donors, asymptomatic carriers (AC), ATL, and HAM/TSP patients using the luciferase immunoprecipitation system.
Immunoreactivity against HBZ was detected in subsets of all HTLV-1-infected individuals but the test did not discriminate between AC, ATL and HAM/TSP. However, the frequency of detection of HBZ-specific antibodies in the serum of ATL patients with the chronic subtype was higher than in ATL patients with the lymphomatous subtype. Antibody responses against HBZ were also detected in cerebrospinal fluid of HAM/TSP patients with anti-HBZ in serum. Antibody responses against HBZ did not correlate with proviral load and HBZ mRNA expression in HAM/TSP patients, but the presence of an HBZ-specific response was associated with reduced CD4+ T cell activation in HAM/TSP patients. Moreover, HBZ-specific antibody inhibited lymphoproliferation in the PBMC of HAM/TSP patients.
This is the first report demonstrating humoral immune response against HBZ associated with HTLV-I infection. Thus, a humoral immune response against HBZ might play a role in HTLV-1 infection.
PMCID: PMC3584941  PMID: 23405908
HTLV-1; Antibody; HAM/TSP; ATL; Asymptomatic carriers; Serum; CSF
14.  Analysis of the T-cell receptor repertoire of human T-cell leukemia virus type 1 (HTLV-1) Tax-specific CD8+ cytotoxic T lymphocytes from patients with HTLV-1-associated disease: evidence for oligoclonal expansion. 
Journal of Virology  1996;70(2):843-851.
Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neurological disease characterized by marked degeneration of the spinal cord and the presence of antibodies against HTLV-1. Patients with HAM/TSP, but not asymptomatic carriers, show very high precursor frequencies of HTLV-1-specific CD8+ T cells in peripheral blood and cerebrospinal fluid, suggestive of a role of these T cells in the pathogenesis of the disease. In HLA-A2+ HAM/TSP patients, HTLV-1-specific T cells were demonstrated to be directed predominantly against one HTLV-1 epitope, namely, Tax11-19. In the present study, we analyzed HLA-A2-restricted HTLV-1 Tax11-19-specific cytotoxic T cells from three patients with HAM/TSP. An analysis of the T-cell receptor (TCR) repertoire of these cells revealed an absence of restricted variable (V) region usage. Different combinations of TCR V alpha and V beta genes were utilized between, but also within, the individual patients for the recognition of Tax11-19. Sequence analysis of the TCR showed evidence for an oligoclonal expansion of few founder T cells in each patient. Apparent structural motifs were identified for the CDR3 regions of the TCR beta chains. One T-cell clone could be detected within the same patient over a period of 3 years. We suggest that these in vivo clonally expanded T cells might play a role in the pathogenesis of HAM/TSP and provide information on HTLV-1-specific TCR which may elucidate the nature of the T cells that infiltrate the central nervous system in HAM/TSP patients.
PMCID: PMC189887  PMID: 8551623
15.  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.
PMCID: PMC3881240  PMID: 24470869
Human T lymphotropic virus type I (HTLV-I); HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP); Immune response
16.  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.
PMCID: PMC3881251  PMID: 24470873
Gene; HAM/TSP; HTLV-I; IL-10; Polymorphisms
17.  Interferon Beta-1a Improves Urinary Symptoms, Reduces Proviral Load, and Modifies the Immune Response in a Patient with HAM/TSP 
The human T-cell lymphotropic virus type 1 (HTLV-1) is the known causative agent of a chronic neurologic condition known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although several therapies have been evaluated for HAM/TSP, none have been approved for use in humans. In this paper, we describe a 55-year-old female patient with HAM/TSP who was treated with interferon beta-1a. This patient, in comparison to 20 female patients with HAM/TSP who were not treated, showed improvement in urinary symptoms over four years of therapy, as well as a reduction in HTLV-1 proviral load and serum cytokine levels typically observed in HAM/TSP. This improved outcome merits further controlled studies on the use and efficacy of interferon beta-1a as a therapy for HAM/TSP.
PMCID: PMC3431060  PMID: 22953092
18.  Effect of Lamivudine on Human T-Cell Leukemia Virus Type 1 (HTLV-1) DNA Copy Number, T-Cell Phenotype, and Anti-Tax Cytotoxic T-Cell Frequency in Patients with HTLV-1-Associated Myelopathy 
Journal of Virology  1999;73(12):10289-10295.
Patients with human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) typically have a high HTLV-1 proviral load in peripheral blood mononuclear cells and abundant, activated HTLV-1-specific cytotoxic T lymphocytes (CTLs). No effective treatment for HAM/TSP has been described so far. We report a 10-fold reduction in viral DNA for five patients with HAM/TSP during treatment with the reverse transcriptase inhibitor lamivudine. In one patient with recent-onset HAM/TSP, the reduction in viral DNA was associated with a fall in the frequency of CTLs specific to two peptides in the immunodominant viral antigen Tax. The half-life of peripheral blood mononuclear cell populations was estimated from changes in viral DNA copy number, CTL frequency, reduction in CD25 expression, and the loss of dicentric chromosomes following radiation-induced damage. Each of these four different techniques indicated a cellular half-life of approximately 3 days consistent with continuous lymphocyte replication and destruction. These results indicate that viral replication through reverse transcription significantly contributes to the maintenance of HTLV-1 viral DNA load. The relative contribution of proliferation versus replication may vary between infected people.
PMCID: PMC113083  PMID: 10559346
19.  HTLV-1 Integration into Transcriptionally Active Genomic Regions Is Associated with Proviral Expression and with HAM/TSP 
PLoS Pathogens  2008;4(3):e1000027.
Human T-lymphotropic virus type 1 (HTLV-1) causes leukaemia or chronic inflammatory disease in ∼5% of infected hosts. The level of proviral expression of HTLV-1 differs significantly among infected people, even at the same proviral load (proportion of infected mononuclear cells in the circulation). A high level of expression of the HTLV-1 provirus is associated with a high proviral load and a high risk of the inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). But the factors that control the rate of HTLV-1 proviral expression remain unknown. Here we show that proviral integration sites of HTLV-1 in vivo are not randomly distributed within the human genome but are associated with transcriptionally active regions. Comparison of proviral integration sites between individuals with high and low levels of proviral expression, and between provirus-expressing and provirus non-expressing cells from within an individual, demonstrated that frequent integration into transcription units was associated with an increased rate of proviral expression. An increased frequency of integration sites in transcription units in individuals with high proviral expression was also associated with the inflammatory disease HAM/TSP. By comparing the distribution of integration sites in human lymphocytes infected in short-term cell culture with those from persistent infection in vivo, we infer the action of two selective forces that shape the distribution of integration sites in vivo: positive selection for cells containing proviral integration sites in transcriptionally active regions of the genome, and negative selection against cells with proviral integration sites within transcription units.
Author Summary
The human leukaemia virus HTLV-1 causes a lifelong infection that cannot be cleared by the immune system. By integrating into the host's DNA, the virus can lie dormant within the cell. The virus can then be reactivated, by processes that are only partly understood, causing the infected cell to multiply and leading to an increase in the quantity of virus in the infected person. In some infected people, the virus is reactivated much faster than in others, and such people are more likely to develop HTLV-1-associated inflammatory diseases such as HAM/TSP, which results in paralysis of the legs. It is not understood what determines this rate of viral reactivation in each person. In this study, we found that integration of HTLV-1 in the host's DNA close to other genes was associated with faster viral reactivation and a higher probability of HAM/TSP. By comparing the viral integration site positions in samples from patients and in cells infected with HTLV-1 in the laboratory, we can identify some of the major forces that allow the virus to persist lifelong whilst avoiding eradication by the immune response.
PMCID: PMC2265437  PMID: 18369476
20.  Human T-lymphotropic virus type 1–associated myelopathy/tropical spastic paraparesis: Viral load and muscle tone are correlated 
Journal of neurovirology  2006;12(6):466-471.
Human T-lymphotropic virus type 1 (HTLV-1) infections are associated with varying degrees of HTLV-1 viral load and spasticity. Increased viral load is associated with higher risk of developing HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP). The authors performed a cross-sectional study of 24 people with HAM/TSP in Lima, Perú, to determine if higher HTLV-1 viral load was correlated with increased muscle tone, measured with a device providing quantitative spasticity assessment (QSA). Median HTLV-1 viral load was 17.0 copies/100 peripheral blood mononuclear cells and QSA value was 39.9 Newton-meters/radian. HTLV-1 viral load was significantly correlated with QSA value (Spearman rho = .48, P = .02), suggesting viral load may play a role in expression of symptomatic neurologic disease. Longitudinal studies are needed to determine if treatments that reduce viral load will reduce muscle tone.
PMCID: PMC2695973  PMID: 17162662
human T-cell lymphotropic virus type 1 (HTLV-1); myelopathy; tropical spastic paraparesis
21.  Association between HLA Class I Alleles and Proviral Load in HTLV-I Associated Myelopathy/Tropical Spastic Paraperesis (HAM/TSP) Patients in Iranian Population 
Objective(s): The aim of this study was to investigate the association between HLA class I alleles (HLA-A*02, HLA-A*24, HLA-Cw*08, HLA-B5401) and proviral load in HTLV-I associated myelopathy/tropical spastic paraperesis (HAM/TSP) patients in Iranian population.
Materials and Methods: 20 new cases of HAM/TSP patients and 30 HTLV-I infected healthy carriers were recruited. Peripheral blood samples were collected. Peripheral blood mononuclear cells (PBMCs) were isolated. DNA was extracted from PBMC.HTLV-I proviral load was calculated by Taqman quantitative real time polymerase chain reaction (qRT-PCR). PCR sequence-specific primer (PCR-SSP) reactions were performed to detect HLA-A, HLA-B and, HLA-Cw alleles.
Results: There was no significant difference in sex and age between asymptomatic and HAM/TSP group. The Mann-Whitney U test was used to compare proviral load between HAM/TSP patients and healthy carrier. Provirus load of HAM/TSP patients was significantly higher than that of HCs (P=0.003, Mann–Whitney U test).Odd ratio was calculated to determine association between class I alleles including (HLA-A*02, HLA-A*24, HLA-Cw*08) and risk of HAM/TSP development. We couldn’t find any association between these class I alleles and risk of HAM/TSP development in our study. In our survey HLA-A*02, HLA-A24, HLA-Cw*08 didn’t have protective effect on proviral load (P=0.075, P=0.060 and 0.650 Mann–Whitney U test respectively).
Conclusion: In conclusion, certain HLA alleles with protective effect in one population may have not similar effect in other population. This may be because of pathogen polymorphism or host genetic heterogeneity and allele frequency in desired population.
PMCID: PMC3881249  PMID: 24470874
HTLV-I; HAM/TSP; HLA; Proviral load
22.  High Expression of CD244 and SAP Regulated CD8+ T Cell Responses of Patients with HTLV-I Associated Neurologic Disease 
PLoS Pathogens  2009;5(12):e1000682.
HTLV-I-specific CD8+ T cells have been characterized with high frequencies in peripheral blood and cerebrospinal fluid and production of proinflammatory cytokines, which contribute to central nervous system inflammation in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, little is known about the differences in CD8+ T cell activation status between asymptomatic carrier (ACs) and patients with HAM/TSP. The expression of CD244, a signaling lymphocyte activation molecule (SLAM) family receptor, was significantly higher on CD8+ T cells in HTLV-I-infected patients, both ACs and patients with HAM/TSP, than those on healthy normal donors (NDs). Blockade of CD244 inhibited degranulation and IFN-γ production in CD8+ T cells of patients with HAM/TSP, suggesting that CD244 is associated with effector functions of CD8+ T cells in patients with HAM/TSP. Moreover, SLAM-associated protein (SAP) was overexpressed in patients with HAM/TSP compared to ACs and NDs. SAP expression in Tax-specific CTLs was correlated in the HTLV-I proviral DNA loads and the frequency of the cells in HTLV-I-infected patients. SAP knockdown by siRNA also inhibited IFN-γ production in CD8+ T cells of patients with HAM/TSP. Thus, the CD244/SAP pathway was involved in the active regulation of CD8+ T cells of patients with HAM/TSP, and may play roles in promoting inflammatory neurological disease.
Author Summary
Human T-lymphotropic virus type I (HTLV-I) is a retrovirus that persistently infects 20 million people worldwide. The majority of infected individuals are asymptomatic carriers of the virus, but 5–10% of infected people develop either adult T cell leukemia/lymphoma (ATL) or a chronic, progressive neurological disease termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is characterized by central nervous system (CNS) inflammation including HTLV-I-specific CD8+ T cells where disease progression and pathogenesis is associated with a dysregulation of antigen-specific CD8+ T cells, although the mechanism of this dysregulation remains to be defined. Here we demonstrate that a signaling lymphocyte activation molecule (SLAM) family of receptors, CD244, was overexpressed on CD8+ T cells of HTLV-I-infected patients than those of healthy normal donors, and that the upregulation of the adaptor protein, SAP, in CD8+ T cells distinguished HTLV-I infected individuals with and without neurologic disease. Both CD244 and SAP were associated with effector functions (high expression of IFN-γ) of CD8+ T cells in patients with HAM/TSP. This finding has important implication for T cell-mediated pathogenesis in human chronic viral infection associated with imbalance of immune function.
PMCID: PMC2779586  PMID: 19997502
23.  CSF CXCL10, CXCL9, and Neopterin as Candidate Prognostic Biomarkers for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis 
Human T-lymphotropic virus type 1 (HTLV-1) -associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. Since the disease course of HAM/TSP varies among patients, there is a dire need for biomarkers capable of predicting the rate of disease progression. However, there have been no studies to date that have compared the prognostic values of multiple potential biomarkers for HAM/TSP.
Methodology/Principal Findings
Peripheral blood and cerebrospinal fluid (CSF) samples from HAM/TSP patients and HTLV-1-infected control subjects were obtained and tested retrospectively for several potential biomarkers, including chemokines and other cytokines, and nine optimal candidates were selected based on receiver operating characteristic (ROC) analysis. Next, we evaluated the relationship between these candidates and the rate of disease progression in HAM/TSP patients, beginning with a first cohort of 30 patients (Training Set) and proceeding to a second cohort of 23 patients (Test Set). We defined “deteriorating HAM/TSP” as distinctly worsening function (≥3 grades on Osame's Motor Disability Score (OMDS)) over four years and “stable HAM/TSP” as unchanged or only slightly worsened function (1 grade on OMDS) over four years, and we compared the levels of the candidate biomarkers in patients divided into these two groups. The CSF levels of chemokine (C-X-C motif) ligand 10 (CXCL10), CXCL9, and neopterin were well-correlated with disease progression, better even than HTLV-1 proviral load in PBMCs. Importantly, these results were validated using the Test Set.
As the CSF levels of CXCL10, CXCL9, and neopterin were the most strongly correlated with rate of disease progression, they represent the most viable candidates for HAM/TSP prognostic biomarkers. The identification of effective prognostic biomarkers could lead to earlier detection of high-risk patients, more patient-specific treatment options, and more productive clinical trials.
Author Summary
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease caused by infection with human T-lymphotropic virus type 1 (HTLV-1). HTLV-1 infects 10–20 million people worldwide, and, depending on the region, 0.25–3.8% of infected individuals develop HAM/TSP. As the disease progresses, chronic inflammation damages the spinal cord and lower limb and bladder function gradually decline. In the worst cases, even middle-aged patients can become perpetually bedridden. Today, there are treatments that may alleviate the symptoms to a certain degree, but there is no cure that can halt disease progression, and there are no known biomarkers to indicate the level and speed of disease progression. In this study, we successfully identified three promising candidate biomarkers. We believe that the use of these biomarkers could lead to more accurate prognoses and more prudent, patient-specific treatment plans. We not only hope that these biomarkers are sensitive enough to use as selection criteria for clinical trials, but also that measurements of these biomarkers can be used to accurately evaluate drug effectiveness. In short, the biomarkers we identified have the potential to help more effectively treat current HAM/TSP patients and to pave the way for new drugs to potentially cure future HAM/TSP patients.
PMCID: PMC3794911  PMID: 24130912
24.  Expansion in CD39+ CD4+ Immunoregulatory T Cells and Rarity of Th17 Cells in HTLV-1 Infected Patients Is Associated with Neurological Complications 
HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develops HAM/TSP. CD4+ T cells are the main target of infection and play a pivotal role in regulating immunity to HTLV and are hypothesized to participate in the pathogenesis of HAM/TSP. The CD39 ectonucleotidase receptor is expressed on CD4+ T cells and based on co-expression with CD25, marks T cells with distinct regulatory (CD39+CD25+) and effector (CD39+CD25−) function. Here, we investigated the expression of CD39 on CD4+ T cells from a cohort of HAM/TSP patients, HTLV-1 asymptomatic carriers (AC), and matched uninfected controls. The frequency of CD39+ CD4+ T cells was increased in HTLV-1 infected patients, regardless of clinical status. More importantly, the proportion of the immunostimulatory CD39+CD25− CD4+ T-cell subset was significantly elevated in HAM/TSP patients as compared to AC and phenotypically had lower levels of the immunoinhibitory receptor, PD-1. We saw no difference in the frequency of CD39+CD25+ regulatory (Treg) cells between AC and HAM/TSP patients. However, these cells transition from being anergic to displaying a polyfunctional cytokine response following HTLV-1 infection. CD39−CD25+ T cell subsets predominantly secreted the inflammatory cytokine IL-17. We found that HAM/TSP patients had significantly fewer numbers of IL-17 secreting CD4+ T cells compared to uninfected controls. Taken together, we show that the expression of CD39 is upregulated on CD4+ T cells HAM/TSP patients. This upregulation may play a role in the development of the proinflammatory milieu through pathways both distinct and separate among the different CD39 T cell subsets. CD39 upregulation may therefore serve as a surrogate diagnostic marker of progression and could potentially be a target for interventions to reduce the development of HAM/TSP.
Author Summary
Human T-lymphotropic virus type 1 (HTLV-1) has been estimated to infect 10–20 million worldwide. The majority of infected individuals are asymptomatic, however, 2% to 3% develop a neurodegenerative disorder called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The reasons why persons with HTLV-1 develop these complications appear to be multiple and complex. Cellular immune response has been implicated in the development of inflammatory alterations in these patients, however the pathogenic mechanisms for disease progression remain unclear. Regulatory CD4+ T cells (Treg) and Th17 cells derive from a common progenitor and conflicting results regarding frequency and function are found in the development of HAM/TSP. The expression of the CD39 ectoenzyme, a molecule that can mediate immunostimulatory and inhibitory effects, is useful to define IL-17 secreting cell populations, suppressive CD4+ T cells and CD4+ T cells with immunostimulatory properties. The interplay of these T-cell subsets may reveal important aspects of HAM/TSP pathogenesis. In this study, we performed an evaluation of the immunoregulatory CD4+ T-cell subsets defined by CD39 expression including Th17 cells. Our results present phenotypic and functional alterations in the CD4+ T cell profile that could account for the transition from asymptomatic status to HAM/TSP, predicting clinical disease risk and tracking disease progression.
PMCID: PMC3566991  PMID: 23409198
25.  High Circulating Frequencies of Tumor Necrosis Factor Alpha- and Interleukin-2-Secreting Human T-Lymphotropic Virus Type 1 (HTLV-1)-Specific CD4+ T Cells in Patients with HTLV-1-Associated Neurological Disease 
Journal of Virology  2003;77(17):9716-9722.
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.
PMCID: PMC187419  PMID: 12915584

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