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Human T-lymphotropic virus type-1 (HTLV-1) persists within hosts via infectious spread (de novo infection) and mitotic spread (infected cell proliferation), creating a population structure of multiple clones (infected cell populations with identical genomic proviral integration sites). The relative contributions of infectious and mitotic spread to HTLV-1 persistence are unknown, and will determine the efficacy of different approaches to treatment. The prevailing view is that infectious spread is negligible in HTLV-1 persistence beyond early infection. However, in light of recent high-throughput data on the abundance of HTLV-1 clones, and recent estimates of HTLV-1 clonal diversity that are substantially higher than previously thought (typically between 104 and 105 HTLV-1+ T cell clones in the body of an asymptomatic carrier or patient with HTLV-1-associated myelopathy/tropical spastic paraparesis), ongoing infectious spread during chronic infection remains possible. We estimate the ratio of infectious to mitotic spread using a hybrid model of deterministic and stochastic processes, fitted to previously published HTLV-1 clonal diversity estimates. We investigate the robustness of our estimates using three alternative estimators. We find that, contrary to previous belief, infectious spread persists during chronic infection, even after HTLV-1 proviral load has reached its set point, and we estimate that between 100 and 200 new HTLV-1 clones are created and killed every day. We find broad agreement between all estimators. The risk of HTLV-1-associated malignancy and inflammatory disease is strongly correlated with proviral load, which in turn is correlated with the number of HTLV-1-infected clones, which are created by de novo infection. Our results therefore imply that suppression of de novo infection may reduce the risk of malignant transformation., Competing Interests: The authors have declared that no competing interests exist.

This study analyzed the relationship between infection by human T-cell lymphotropic virus type 1 (HTLV-1) and changes in the pulmonary system. Cohort and case-control study models that analyzed a causal association between HTLV-1 and changes in the pulmonary system were considered. There were no restrictions on language and publication period. The study was registered in the PROSPERO systematic analysis database (Protocol No. CRD42017078236) and was prepared according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The following databases were used: PubMed, BVS Regional Portal, Embase, CINAHL and Web of Science. We utilized the Newcastle-Ottawa Scale to assess the methodological quality of published studies and the Kappa coefficient to assess the agreement level between two reviewers. Of the total 1156 studies retrieved by the search strategy, 28 were considered potentially eligible (Kappa test = 0.928). Of the 28 studies, three fully met the inclusion criteria. These indicated that pulmonary lesions, such as bronchiectasis and bronchitis/bronchiolitis, were observed in patients with HTLV-1, with high-resolution computed tomography of the chest being the main method of diagnostic investigation. The analyzed cohort and case-control studies indicated an etiological relationship between HTLV-1 infection and the presence of lung lesions, with emphasis on bronchiectasis in the presence of high viral loads, as well as a higher mortality in these individuals compared with the general population., Competing Interests: Declaration of competing interest This research did not receive any specific subsidies from funding agencies in the public, commercial or non-profit sectors. PhD. V.M.F.N. received a scholarship awarded by the State University of Pará. All authors report no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We investigate the possible effects of acupuncture on the improvement of neurological problems in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP)disease. Twenty patients with HAM/TSP were studied in this pre and post-test clinical trial. Urinary incontinence, global motor disability, spasticity, and pain severity were evaluated before, one month, and three-month after the intervention. Analyses demonstrated a significant reduction of urinary symptoms one month after acupuncture (P = 0.023). A significant improvement was observed in patients' pain and the spasticity at the upper extremity joints, one and three-month after the intervention (P < 0.05). This study suggests that body acupuncture can be used as a complementary treatment to improve HAM/TSP neurological symptoms.

Human T cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. The HTLV-1 bZIP factor (HBZ) gene is constantly expressed in HTLV-1 infected cells and ATL cells. HBZ protein suppresses transcription of the tax gene through blocking the LTR recruitment of not only ATF/CREB factors but also CBP/p300. HBZ promotes transcription of Foxp3, CCR4, and T-cell immunoreceptor with Ig and ITIM domains (TIGIT). Thus, HBZ is critical for the immunophenotype of infected cells and ATL cells. HBZ also functions in its RNA form. HBZ RNA suppresses apoptosis and promotes proliferation of T cells. Since HBZ RNA is not recognized by cytotoxic T cells, HTLV-1 has a clever strategy for avoiding immune detection. HBZ plays central roles in maintaining infected T cells in vivo and determining their immunophenotype.

Purpose: Vestibular Myogenic Evoked Potential (VEMP) evaluates vestibulo-ocular and vestibulo-collic reflexes involved in the function of the otolithic organs and their afferent pathways. We compared the results of cervical and ocular VEMP in HTLV-1 associated myelopathy (HAM) and HTLV-1-asymptomatic infection., Participants and Methods: This cross-sectional study included 52 HTLV-1-infected individuals (26 HAM and 26 asymptomatic carriers) and 26 seronegative controls. The groups were similar regarding age and gender. Participants underwent simultaneous ocular and cervical VEMP. The stimulus to generate VEMP was a low-frequency tone burst sound tone burst, with an intensity of 120 decibels normalized hearing level, bandpass filter from 10 to 1,500 Hertz (Hz), with 100 stimuli at 500 Hz and 50 milliseconds recording time. The latencies of the electrophysiological waves P13 and N23 for cervical VEMP and N10 and P15 waves for ocular VEMP were compared among the groups. The absence or delay of the electrophysiological waves were considered abnormal results., Results: Ocular VEMP was similar among the groups for N10 (p = 0.375) and different for P15 (p≤0.001). Cervical VEMP was different for P13 (p = 0.001) and N23 (p = 0.003). About ocular VEMP, in the HTLV-1-asymptomatic group, normal waves were found in 23(88.5%) individuals; in HAM group, normal waves were found in 7(26.9%). About cervical VEMP, 18(69.2%) asymptomatic carriers presented normal waves and only 3(11.5%) patients with HAM presented normal waves. Abnormalities in both VEMPs were found in 1(3.8%) asymptomatic carrier and in 16(61.5%) patients with HAM., Conclusion: Neurological impairment in HAM was not restricted to the spinal cord. The mesencephalic connections, tested by ocular VEMP, have been also altered. Damage of the oculomotor system, responsible for eye stabilization during head and body movements, may explain why dizziness is such a frequent complaint in HAM., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Bowel dysfunction is frequent in patients with spinal cord diseases, but little is known about the prevalence of bowel symptoms in human T-lymphotropic virus-(HTLV-1) infected individuals. The purpose of this study is to determine the frequency of bowel symptoms in HTLV-1 infected individuals and their correlation with the degree of neurologic disease., Methods: This is a cross-sectional study comparing the frequency of bowel symptoms in HTLV-1-infected individuals* and seronegative donors (controls). Patients answered a questionnaire, the Rome III Criteria was applied, and stool consistency was evaluated by the Bristol Stool Form Scale. The individuals were classified as HTLV-1 carriers, probable HTLV-1 myelopathy and definitive HTLV-1 associated myelopathy or tropical spastic paraparesis (definitive HAM / TSP)**., Results: We studied 72 HTLV-1 infected individuals and 72 controls with equal age and gender distribution. Constipation was the most frequent complaint, occurring in 38 % of HTLV-1 individuals and in 15 % of the controls. In comparison to the seronegative controls, the probability of constipation occurrence was approximately 18 times higher in definitive HAM / TSP patients. Straining, lumpy or hard stools, sensation of anorectal obstruction/blockage, fewer than 3 defecations per week, flatulence, soiling, evacuation pain, and bleeding were also more frequent in the HTLV-1 patients than in the controls. Moreover, bowel symptoms were more frequent in patients with definitive or probable HAM / TSP than in carriers., Conclusions: Bowel symptoms were more frequent in HTLV-1-infected patients than in seronegative controls and the frequency of bowel symptoms correlated with the severity of neurologic disease.

One of the prominent features of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the excessive recruitment of leukocytes to the central nervous system (CNS), which leads to an inflammatory response-with chemokines and their receptors playing the main role in this recruitment. The aim of the study was to examine the relation of CXCR1 and CXCR2, both of which are involved in the trafficking of lymphocytes into the CNS, with the outcome of HTLV-1 infection. The mRNA levels of CXCR1 and CXCR2 were examined in peripheral blood mononuclear cells (PBMCs) of HAM/TSP patients, HTLV-1 asymptomatic carriers (ACs), and healthy controls (HCs). Furthermore, the frequency of CD4 + and CD8 + T cells expressing CXCR1 and CXCR2 was evaluated in the studied groups. The results of the present study showed a substantial increase in the mean mRNA expression of CXCR2 in the HAM/TSP patients compared to the HCs and ACs (p < 0.001). A positive correlation was also found between PVL and CXCR2 mRNA expression in the total population of HTLV-1-infected subjects (R = 0.526, p < 0.001). Moreover, the percentage of CD8 + CXCR2-expressing cells was higher in HAM/TSP patients compared to ACs and HCs (p < 0.05, p < 0.01, respectively). Although the percentage of CD4 + CXCR2-expressing cells was higher in HAM/TSP patients than in ACs and HCs, a significant difference was only found between HAM/TSP patients and HCs (p < 0.05). No significant difference in the CXCR1 mRNA expression was observed in the studied groups. The frequency of the CD8 + CXCR1- and CD4 + CXCR1-expressing cells was significantly lower in HAM/TSP patients than in ACs and HCs (p < 0.001 and p < 0.01, respectively). In conclusion, the high frequency of CXCR2 CD8 + T cells and the high levels of CXCR2 mRNA expression in HAM/TSP patients are associated with disease pathogenesis, while the high frequencies of CXCR1 T cells in ACs might suggest that these cells act as effector CD8 T cells and are involved in controlling the viral spread and modulation of the immune response.

The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus from the Retroviridae family that infects cluster of differentiation 4 (CD4) T-lymphocytes and stimulates their proliferation. A severe consequence of this infection can be the HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is associated with a progressive demyelinating disease of the upper motor neurons. The HAM/TSP conditions frequently present with neurological complaints such as gait impairment, sphincter disturbances, and several sensory losses. We compared findings from the posturographic evaluation from the asymptomatic HTLV-1 infected subjects, HTLV-1 infected subjects having HAM/TSP, and control group database. A force plate was used to record the postural oscillations. Analysis of variance and multivariate linear discriminant analysis were used to compare the data obtained from the three groups of participants. In general, HAM/TSP patients had worse postural balance control than did the HTLV-1 patients and the controls (p < 0.05). We found that in six out of ten parameters of the postural balance control, there was a gradual increase in impairment from control to HTLV-1 to HAM/TSP groups. All parameters had higher values with the subject's eyes closed. The multivariate linear discriminant analysis showed there was a reasonable difference in results between the control and HAM/TSP groups, and the HTLV-1 group was at the intersecting area between them. We found that HAM/TSP patients had worse balance control than did HTLV-1 infected patients and the control group, but asymptomatic HTLV-1 infected patients represent an intermediate balance control status between controls and HAM/TSP patients. Posturographic parameters can be relied on to identify subtle changes in the balance of HTLV-1 patients and to monitor their functional loss. HTLV-1 is a tropical disease that can be transmitted by sexual intercourse, blood transfusion, and breast-feeding. Some infected subjects develop an HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a condition characterized by spasticity, weakness in lower limbs, and difficulty in walking long distances and going up and down the stairs, besides the history of falls. We compared the body oscillations using a force plate to investigate the postural balance control. HTLV-1 infected patients had imbalance that could be identified by posturographic parameters. Patients with HAM/TSP clearly had balance impairments, while HTLV-1 without HAM/TSP had a subtle impairment that was not seen on clinical scales, suggesting that these patients were in the middle between healthy and HAM/TSP patients, and carried a risk of developing severe imbalance postural control. We suggest that more research should be done with the aim to identify the subtle signs in asymptomatic HTLV-1 patients to investigate if this group of patients need attention similar to the HAM/TSP patients.

Background: Although classical human T-cell lymphocyte virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis syndrome is the most frequent HTLV-1-associated neurological disorder, some "minor" neurological disorders can be seen in "asymptomatic" carriers. These disorders, including cognitive alterations already described in clinical cases and studies, may constitute an intermediate syndrome (IMS) between the asymptomatic state and myelopathy. The aim of this study was to investigate the presence of cognitive deficits in patients with HTLV-1 virus, who usually are diagnosed as asymptomatic., Methods: A total of 54 HTLV-1-infected patients were evaluated, 35 asymptomatic and 19 with minor neurological alterations (evaluated by a neurologist); 25 HTLV-1-seronegative individuals served as controls. The instruments used were: Beck's Depression Inventory, Lawton's Daily Life Activity Scale, and a complete neuropsychological battery. The application of these evaluation instruments was performed blindly, with the evaluator neuropsychologist not knowing the clinical condition of the patient., Results: Most of the participants in this cohort, including seronegative controls, were female (n = 57, 72.21%), their mean age was 52.34 years (SD = 14.29) and their average schooling was 9.70 years (SD = 4.11)., Discussion: Participants classified with IMS had lower gross scores when compared with both the patients classified as asymptomatic and with the control group, and when tested for auditory episodic memory of immediate (p < 0.01), and late (p = 0.01), recall., Conclusion: Patients with IMS presented with memory impairment when compared with asymptomatic patients and seronegative individuals; this is one of the symptoms that aids in the classification of the syndrome.

Background: We reported that human T cell leukemia virus 1 (HTLV-1) infection is positively associated with atherosclerosis. Recent evidence has revealed a close association of periodontitis with atherosclerosis, endothelial dysfunction, and disruption of the microcirculation. However, the association between HTLV-1 and advanced periodontitis has not been investigated to date. Since hematopoietic activity is closely linked to endothelial maintenance activity and is known to decline with age, we hypothesized that the state of hematopoietic activity influenced the association between HTLV-1 and advanced periodontitis in elderly participants., Methods: A cross-sectional study was performed including 822 elderly participants aged 60-99 years who participated in a dental health check-up. Advanced periodontitis was defined as a periodontal pocket ≥ 6.0 mm. Participants were classified as having low or high hematopoietic activity according to the median values of reticulocytes., Results: HTLV-1 infection was positively related to advanced periodontitis among participants with lower hematopoietic activity (lower reticulocyte count), but not among participants with higher hematopoietic activity (higher reticulocyte count). The adjusted odds ratio (95% confidence interval) considering potential confounding factors was 1.92 (1.05-3.49) for participants with a lower reticulocyte count and 0.69 (0.35-1.36) for participants with a higher reticulocyte count., Conclusions: Among elderly participants, the association between HTLV-1 infection and advanced periodontitis is influenced by hematopoietic activity. Since hematopoietic activity is associated with endothelial maintenance, these findings provide an efficient tool for clarifying the underlying mechanism of the progression of periodontitis among elderly participants.

Background: Human retroviruses HIV and HTLV share transmission routes. HIV widely spread in Spain during the 80 s through injection drug use and sex, and nowadays HIV rates in Spain account for one of the largest in Europe. In contrast, HTLV-1 is not endemic in Spain, despite hosting huge numbers of migrants from highly endemic regions. Herein, we report the rate and main features of the HIV-HTLV co-infected population in Spain., Methods: A national registry exists in Spain for HTLV since year 1989. Data from standardized case report forms and one centralized lab repository were reviewed, especially for the subset with HTLV-HIV co-infection., Results: Up to December 2018, a total of 369 individuals with HTLV-1 had been diagnosed in Spain. 64% of the population were females, and Latin American individuals accounted for 64.5%. Classical HTLV-associated illnesses were found in 12.7% (myelopathy) and 7.6% (leukemia). HIV coinfection was found in 12 (3.2%). Of those, 3 patients (25%) were female and 39 (75%) were of non-Spanish origin. All but two harbored HIV-1 subtype B, being non-B variants found in the two West Africans. Exposure had been sexual in most cases, being 4 homosexual men. Seven HTLV-HIV co-infected patients had developed AIDS and two had developed myelopathy. There was no evidence for increased HTLV-1 clinical pathogenicity due to HIV coinfection., Conclusion: HIV coinfection is infrequent (<5%) among HTLV-1 carriers in Spain. More than half of co-infected patients come from Latin America. Sexual contact is the most frequent risk behavior, being MSM one third of cases. Late diagnosis explains the high rate (9/12) of clinical manifestations in our HIV-HTLV co-infected population., (Copyright © 2019 Elsevier B.V. All rights reserved.)

An estimated 10-20 million people worldwide are infected with human T cell leukemia virus type 1 (HTLV-1), with endemic areas of infection in Japan, Australia, the Caribbean, and Africa. HTLV-1 is the causative agent of adult T cell leukemia (ATL) and HTLV-1 associated myopathy/tropic spastic paraparesis (HAM/TSP). HTLV-1 expresses several regulatory and accessory genes that function at different stages of the virus life cycle. The regulatory gene Tax-1 is required for efficient virus replication, as it drives transcription of viral gene products, and has also been demonstrated to play a key role in the pathogenesis of the virus. Several studies have identified a PDZ binding motif (PBM) at the carboxyl terminus of Tax-1 and demonstrated the importance of this domain for HTLV-1 induced cellular transformation. Using a mass spectrometry-based proteomics approach we identified sorting nexin 27 (SNX27) as a novel interacting partner of Tax-1. Further, we demonstrated that their interaction is mediated by the Tax-1 PBM and SNX27 PDZ domains. SNX27 has been shown to promote the plasma membrane localization of glucose transport 1 (GLUT1), one of the receptor molecules of the HTLV-1 virus, and the receptor molecule required for HTLV-1 fusion and entry. We postulated that Tax-1 alters GLUT1 localization via its interaction with SNX27. We demonstrate that over expression of Tax-1 in cells causes a reduction of GLUT1 on the plasma membrane. Furthermore, we show that knockdown of SNX27 results in increased virion release and decreased HTLV-1 infectivity. Collectively, we demonstrate the first known mechanism by which HTLV-1 regulates a receptor molecule post-infection., Competing Interests: The authors have declared that no competing interests exist.

Background: The human T-lymphotropic virus type 1 (HTLV-1) affects 2-5 million people worldwide, and is associated with a number of degenerative and infectious diseases. The Envelope glycoproteins (gp) are highly conserved among the different HTLV-1 isolates, although nucleotide substitutions in the region that codifies these proteins may influence both the infectivity and the replication of the virus. The gp46 gene has functional domains which have been associated with the inhibition of the formation of the syncytium, cell-cell transmission, and the production of antibodies. The present study investigated the genetic stability of the gp46 gene of HTLV-1 in an endemic region of Brazilian Amazonia., Methods: Index case (IC - a sample of a given family group) carriers of HTLV-1 were investigated in the metropolitan region of Belém (Pará, Brazil) between January 2010 (registered retrospectively) and December 2015. The sequences that codify the gp46 were amplified by PCR, purified and sequenced (MF084788-MF084825). The gene was characterized using bioinformatics and Bayesian Inference., Results: The 40 patients analyzed had a mean age of 45.2 years and 70% presented some type of symptom, with a predominance of pain and sensitivity, dysautonomia, and motor disorders. All patients presented the aA (Transcontinental Cosmopolitan) genotype, with an extremely low mutation rate, which is characteristic of the codifying region (aA - 1.83 × 10- 4 mutations per site per year). The gp46 gene had a nucleotide diversity of between 0.00% and 2.0%. Amino acid mutations were present in 66.6% of the samples of individuals with signs/symptoms or diseases associated with HTLV-1 (p = 0.0091). Of the three most frequent mutations, the previously undescribed N93D mutant was invariably associated with symptomatic cases., Conclusions: The aA HTLV-1 subtype is predominant in the metropolitan region of Belém and presented a high degree of genetic stability in the codifying region. The rare N93D amino acid mutation may be associated with the clinical manifestations of this viral infection., Importance: Little is known of the phylogeny of HTLV-1 in the endemic region of Brazilian Amazonia, and few complete gene sequences are available for the gp46 glycoprotein from the local population. The nucleotide sequences of the viral gp46 gene recorded in the present study confirmed the genetic stability of the region, and pointed to a homogeneous viral group, with local geographic characteristics. Further research will be necessary to more fully understand the molecular diversity of this protein, given the potential of this codifying region as a model for an effective HTLV-1 vaccine. The identification of a rare mutation (N93D), present only in symptomatic patients, should also be investigated further as a potential clinical marker., Trial Registration: ISRCTN 12345678, registered 28 September 2014.

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.

Rationale: There are roughly 5 to 10 million persons infected with human T-lymphotropic virus type 1 (HTLV-1) worldwide, and the safety of treating this population with biologics remains poorly understood., Patient Concerns and Diagnosis: An HTLV-1-infected 66-year-old female with HTLV-1 uveitis (HU) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Her HU had been in remission and her HAM/TSP symptoms had been managed effectively with oral steroids for years. However, she developed severe rheumatoid arthritis (RA) after failing to respond well to conventional anti-rheumatic agents., Interventions: She was administered two intravenous 8mg/kg doses of the biologic tocilizumab., Outcomes: Subsequently, her RA symptoms resolved, but she suffered a recurrence of HU and exacerbation of HAM/TSP symptoms. When she was switched back to steroid-based treatment, HU and HAM symptoms both improved, but RA symptoms again worsened. Finally, an attempt to substitute the biologic abatacept and reduce the steroids failed when HAM/TSP symptoms again became aggravated., Lessons: To the best of our knowledge, this represents the first report worldwide of a biologic aggravating HTLV-1-associated conditions. This report suggests that caution is advised when using biologics to treat HTLV-1-infected patients, though further research is required to clarify the situation.

HTLV-1 creates a chronic health condition that involves moderate to severe pain with a negative impact on quality of life (QoL). There is no consensus on which attitudes to pain are more related to the worsening of QoL in HTLV-1 infected patients. The aim of this study was to investigate the correlation between QoL and multidimensional aspects of pain in patients with HTLV-1. A cross-sectional study was conducted in Salvador, Bahia, Brazil. The study included individuals diagnosed with HTLV-1. The Short Form 36 Questionnaire was used to analyze QoL, and the Brief Pain Inventory was used to assess multidimensional aspects of pain. The mean pain intensity was 4.88±3.06 on the visual pain scale, and the average impact on QoL corresponded to a loss of approximately 40%. Moderate to high correlations between pain intensity and all domains of QoL were observed and compared reaction attitudes for general activity, mood, ability to walk, ability to work, relationships, sleep, and ability to enjoy life (r>0.40; p<0.05). Moderate correlations were found between all domains of QoL, pain intensity, and reactive attitudes to pain. The greatest pain intensity impacts involved difficulty to walk and to work, and interpersonal relationships in the emotional aspect of QoL., (Copyright © 2016 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.)

Background: The human T-Cell Lymphotropic Virus Type 1 (HTLV-1) is a retrovirus associated with neurological alterations; individuals with HTLV-1 infection may develop HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM/TSP). Frequent neurological complaints include foot numbness and leg weakness. In this study, we compared the distribution of the body weight on different areas of the foot in HTLV-1 patients with HAM/TSP, asymptomatic HTLV-1 patients, and healthy individuals., Methodology: We studied 36 HTLV-1 infected patients, who were divided in two groups of 18 patients each based on whether or not they had been diagnosed with HAM/TSP, and 17 control subjects. The evaluation included an interview on the patient's clinical history and examinations of the patient's reflexes, foot skin tactile sensitivity, and risk of falling. The pressure distribution on different areas of the foot was measured with baropodometry, using a pressure platform, while the patients had their eyes open or closed., Main Findings: The prevalence of neurological disturbances-altered reflexes and skin tactile sensitivity and increased risk of falling-was higher in HTLV-1 HAM/TSP patients than in HTLV-1 asymptomatic patients. The medium and maximum pressure values were higher in the forefoot than in the midfoot and hindfoot in both HTLV-1 groups. In addition, the pressure on the hindfoot was lower in HAM/TSP patients compared to control subjects., Conclusions: The neurological disturbances associated with HTLV-1 infection gradually worsened from HTLV-1 asymptomatic patients to HAM/TSP patients. Baropodometry is a valuable tool to establish the extent of neurological damage in patients suffering from HTLV-1 infection.

The human T-cell leukemia retrovirus type-1 (HTLV-1) p30(II) protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation. We have previously demonstrated that p30(II) interacts with the c-MYC oncoprotein and enhances c-MYC-dependent transcriptional and oncogenic functions. However, the molecular and biochemical events that mediate the cooperation between p30(II) and c-MYC remain to be completely understood. Herein we demonstrate that p30(II) induces lysine-acetylation of the c-MYC oncoprotein. Acetylation-defective c-MYC Lys→Arg substitution mutants are impaired for oncogenic transformation with p30(II) in c-myc(-/-) HO15.19 fibroblasts. Using dual-chromatin-immunoprecipitations (dual-ChIPs), we further demonstrate that p30(II) is present in c-MYC-containing nucleoprotein complexes in HTLV-1-transformed HuT-102 T-lymphocytes. Moreover, p30(II) inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. These findings suggest that c-MYC-acetylation is required for the cooperation between p30(II)/c-MYC which could promote proviral replication and contribute to HTLV-1-induced carcinogenesis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The mechanisms involved in the persistence of activated CD4+ T lymphocytes following primary human T leukemia/lymphoma virus type 1 (HTLV-1) infection remain unclear. Here, we demonstrate that the HTLV-1 Tax oncoprotein modulates phosphorylation and transcriptional activity of the FOXO3a transcription factor, via upstream activation of the AKT pathway. De novo HTLV-1 infection of CD4+ T cells or direct lentiviral-mediated introduction of Tax led to AKT activation and AKT-dependent inactivation of FOXO3a, via phosphorylation of residues Ser253 and Thr32. Inhibition of FOXO3a signalling led to the long-term survival of a population of highly activated, terminally differentiated CD4+Tax+CD27negCCR7neg T cells that maintained the capacity to disseminate infectious HTLV-1. CD4+ T cell persistence was reversed by chemical inhibition of AKT activity, lentiviral-mediated expression of a dominant-negative form of FOXO3a or by specific small interfering RNA (siRNA)-mediated silencing of FOXO3a. Overall this study provides new mechanistic insight into the strategies used by HTLV-1 to increase long-term maintenance of Tax+CD4+ T lymphocytes during the early stages of HTLV-1 pathogenesis.

Objective: We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) on chronic pain in human T-lymphotropic virus type I-infected patients., Materials and Methods: This is a sham-controlled randomized clinical trial. Twenty participants were randomized to receive active or sham anodal tDCS over the primary motor cortex (M1), with 2 mA, 25 cm electrodes, for 20 minutes on 5 consecutive days. Pain intensity was measured at baseline and after each day of treatment using a Visual Analog Scale. Associated factors such as pain components description, pressure pain threshold, and Timed Up and Go task were also assessed., Results: Mild adverse events were reported by 100% of patients in the tDCS group and 90% in the sham group. Comparison of daily Visual Analog Scale pain scores from both groups demonstrated a significant effect for the factor Time (P<0.001), but not for Group (P=0.13) or Time×Group interaction (P=0.06). There were 8 (80%) responders (reduction of 50% or more in pain intensity) in the tDCS group and 3 (30%) in the sham group (P=0.03). Both groups demonstrated improvements for most associated factors evaluated. However, there was no difference in between-groups comparison analyses., Conclusions: The analysis of the main outcomes in this study did not demonstrate a significant advantage of anodal tDCS applied to M1 in patients with human T-lymphotropic virus type I and chronic pain in comparison with sham tDCS, although secondary analysis suggests some superiority of active tDCS over sham. The large placebo effect observed in this study may explain the small differences between sham versus active tDCS.

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. The HTLV-1 transactivator protein Tax controls many critical cellular pathways, including host cell DNA damage response mechanisms, cell cycle progression, and apoptosis. Extracellular vesicles called exosomes play critical roles during pathogenic viral infections as delivery vehicles for host and viral components, including proteins, mRNA, and microRNA. We hypothesized that exosomes derived from HTLV-1-infected cells contain unique host and viral proteins that may contribute to HTLV-1-induced pathogenesis. We found exosomes derived from infected cells to contain Tax protein and proinflammatory mediators as well as viral mRNA transcripts, including Tax, HBZ, and Env. Furthermore, we observed that exosomes released from HTLV-1-infected Tax-expressing cells contributed to enhanced survival of exosome-recipient cells when treated with Fas antibody. This survival was cFLIP-dependent, with Tax showing induction of NF-κB in exosome-recipient cells. Finally, IL-2-dependent CTLL-2 cells that received Tax-containing exosomes were protected from apoptosis through activation of AKT. Similar experiments with primary cultures showed protection and survival of peripheral blood mononuclear cells even in the absence of phytohemagglutinin/IL-2. Surviving cells contained more phosphorylated Rb, consistent with the role of Tax in regulation of the cell cycle. Collectively, these results suggest that exosomes may play an important role in extracellular delivery of functional HTLV-1 proteins and mRNA to recipient cells., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Adult T-cell leukemia/lymphoma is a rare mature CD4(+) T-cell neoplasm caused by the retrovirus human T-lymphotrophic virus type 1. At present there are approximately 20 million people infected globally with this virus, and most of these individuals belong to the endemic areas in southern Japan, Africa, the Caribbean basin, and Latin America. In the United States, it is usually seen in immigrants from these endemic regions. Adult T-cell leukemia/lymphoma predominantly affects the adult population and is rare in children. Adult T-cell leukemia/lymphoma has 4 subtypes: acute, lymphomatous, chronic, and smoldering. Clinically, the first 2 variants are classified as aggressive, and the latter two are classified as indolent. Given the rare occurrence and diagnostic challenges associated with adult T-cell leukemia/lymphoma, this review will highlight its salient features to aid in recognition of this entity and perform a comprehensive diagnostic workup.

The typical characteristics of mesenchymal stem cells (MSCs) can be affected by inflammatory microenvironment; however, the exact contribution of HTLV-1 to MSC dysfunction remains to be elucidated. In this study, we demonstrated that MSC cell surface molecules VCAM-1 and ICAM-1 are upregulated by contact with HTLV-1, and HLA-DR was most highly expressed in MSCs co-cultured with MT2 cells. The expression levels of VCAM-1 and HLA-DR were increased in MSCs cultured in the presence of PBMCs isolated from HTLV-1-infected symptomatic individuals compared with those cultured with cells from asymptomatic infected individuals or healthy subjects. HTLV-1 does not impair the MSC differentiation process into osteocytes and adipocytes. In addition, MSCs were efficiently infected with HTLV-1 in vitro through direct contact with HTLV-1-infected cells; however, cell-free virus particles were not capable of causing infection. In summary, HTLV-1 can alter MSC function, and this mechanism may contribute to the pathogenesis of this viral infection., (© 2013 Published by Elsevier Inc.)

Adult T-cell leukemia (ATL) is an aggressive malignancy of peripheral T cells infected with human T-cell leukemia virus type 1 (HTLV-1). The prognosis of patients with aggressive ATL remains poor because ATL cells acquire resistance to conventional cytotoxic agents. Therefore, development of novel agents is urgently needed. We examined the effects of resveratrol, a well-known polyphenolic compound, on cell proliferation and survival of HTLV-1-infected T-cell lines, MT-2 and HUT-102. We found that resveratrol suppressed cell proliferation and induced cell death of MT-2 and HUT-102 cells. Immunoblot analysis showed inhibition of myeloid cell leukemia sequence (Mcl)-1 and cellular inhibitor of apoptosis protein (cIAP)-2 expression as well as signal transducers and activators of transcription (STAT) 3 phosphorylation at Tyr(705) and Ser(727) in resveratrol-treated cells. We also observed cleavage of caspase-3 and poly(ADP-ribose) polymerase in resveratrol-treated cells, indicating that resveratrol induces caspase-dependent apoptosis in MT-2 and HUT-102 cells. In addition, the STAT3 inhibitor S3I-201 not only induced cell growth arrest and cell death but also activated caspase-3 in MT-2 and HUT-102 cells, indicating that STAT3 may be a therapeutic target for ATL. These results suggest that resveratrol presents a potent anti-proliferative effect in part via the suppression of STAT3 phosphorylation and Mcl-1 and cIAP-2 expression in HTLV-1-infected T cells. Resveratrol merits further investigation as a potential chemotherapeutic agent for ATL., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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

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.

Background: Other studies have reported high rates of depression and anxiety among human T-lymphotropic virus Type I (HTLV-I)-infected subjects and have even suggested that HTLV-I causes psychiatric disease., Study Design and Methods: We interviewed HTLV-I, HTLV-II, and demographically similar HTLV-seronegative blood donors with the Mini-International Neuropsychiatric Interview. Prevalences of major depression and generalized anxiety disorder in each group were calculated and compared to published US population data. Adjusted odds ratios (aOR) and 95% confidence intervals (CIs) controlling for educational achievement, alcohol intake, and self-reported health status were calculated with multivariate logistic regression., Results: Major depression was diagnosed in five (5.4%) of 93 HTLV-I-positive subjects (aOR, 2.19; 95% CI, 0.63-7.55) and 17 (6.6%) of 256 HTLV-II-positive subjects (aOR, 1.61; 95% CI, 0.66-3.927), compared to 12 (2.1%) of 585 HTLV-seronegative blood donors. The prevalence of major depression among infected subjects was comparable to the 6.7% prevalence in the US general population. Generalized anxiety disorder was diagnosed in five (5.4%) HTLV-I-positive subjects (OR, 2.32; 95% CI, 0.74-7.26) and 12 (4.7%) HTLV-II-positive subjects (OR, 1.65; 95% CI, 0.68-4.01), compared to 15 (2.6%) seronegative subjects and 3.1% in the US general population., Conclusion: Major depression and generalized anxiety disorder were not significantly more prevalent among HTLV-I- and HTLV-II-infected former blood donors after controlling for health status and other confounding variables. HTLV-seronegative blood donors had lower prevalences of these conditions than the US population, probably due to a "healthy blood donor effect.", (© 2012 American Association of Blood Banks.)

The HTLV-1 oncoprotein Tax is a potent activator of classical and alternative NF-κB pathways and is thought to promote cell proliferation and transformation via NF-κB activation. We showed recently that hyperactivation of NF-κB by Tax triggers a cellular senescence response (H. Zhi et al., PLoS Pathog. 7:e1002025, 2011). Inhibition of NF-κB activation by expression of I-κBα superrepressor or by small hairpin RNA (shRNA)-mediated knockdown of p65/RelA rescues cells from Tax-induced rapid senescence (Tax-IRS). Here we demonstrate that Tax-IRS is driven by the transcriptional activity of NF-κB. Knockdown of IKKγ, the primary Tax target, by shRNAs abrogated Tax-mediated activation of both classical and alternative NF-κB pathways and rendered knockdown cells resistant to Tax-IRS. Consistent with a critical role of IKKα in the transcriptional activity of NF-κB, IKKα deficiency drastically decreased NF-κB trans-activation by Tax, although it only modestly reduced Tax-mediated I-κBα degradation and NF-κB nuclear localization. In contrast, although IKKβ knockdown attenuated Tax-induced NF-κB transcriptional activation, the residual NF-κB activation in IKKβ-deficient cells was sufficient to trigger Tax-IRS. Importantly, the phenotypes of NIK and TAK1 knockdown were similar to those of IKKα and IKKβ knockdown, respectively. Finally, double knockdown of RelB and p100 had a minor effect on senescence induction by Tax. These data suggest that Tax, through its interaction with IKKγ, helps recruit NIK and TAK1 for IKKα and IKKβ activation, respectively. In the presence of Tax, the delineation between the classical and alternative NF-κB pathways becomes obscured. The senescence checkpoint triggered by Tax is driven by the transcriptional activity of NF-κB, which depends on activated IKKα and p65/RelA.

Background: In vitro studies have demonstrated that deletions and point mutations introduced into each 21 bp imperfect repeat of Tax-responsive element (TRE) of the genuine human T-cell leukemia virus type I (HTLV-1) viral promoter abolishes Tax induction. Given these data, we hypothesized that similar mutations may affect the proliferation of HTLV-1-infected cells and alter the proviral load (PvL). To test this hypothesis, we conducted a cross-sectional genetic analysis to compare the near-complete LTR nucleotide sequences that cover the TRE1 region in a sample of HTLV-1 asymptomatic carriers with different PvL burden., Methods: A total of 94 asymptomatic HTLV-1 carriers with both sequence from the 5' long terminal repeat (LTR) and a PvL for Tax DNA measured using a sensitive SYBR Green real-time PCR were studied. The 94 subjects were divided into three groups based on PvL measurement: 31 low, 29 intermediate, and 34 high. In addition, each group was compared based on sex, age, and viral genotypes. In another analysis, the median PvLs between individuals infected with mutant and wild-type viruses were compared., Results: Using a categorical analysis, a G232A substitution, located in domain A of the TRE-1 motif, was detected in 38.7% (12/31), 27.5% (8/29), and 61.8% (21/34) of subjects with low, intermediate, or high PvLs, respectively. A significant difference in the detection of this mutation was found between subjects with a high or low PvL and between those with a high or intermediate PvL (both p < 0.05), but not between subjects with a low or intermediate PvL (p > 0.05). This result was confirmed by a non-parametric analysis that showed strong evidence for higher PvLs among HTLV-1 positive individuals with the G232A mutation than those without this mutation (p < 0.03). No significant difference was found between the groups in relation to age, sex or viral subtypes (p > 0. 05)., Conclusions: The data described here show that changes in domain A of the HTLV-1 TRE-1 motif resulting in the G232A mutation may increase HTLV-1 replication in a majority of infected subjects.

Human T-lymphotropic virus-1 (HTLV-1) causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia-lymphoma in individuals with dysfunctional immune responses. In this study, to characterize the HTLV-1-specific cytotoxic T lymphocyte (CTL) populations in asymptomatic HTLV-1 carriers (ACs), HAM/TSP patients, and carriers with autoimmune disorders (CAIDs), we examined the role of programmed death-1 and its ligand (PD-1/PD-L1) in HTLV-1-specific CTL functions using an HTLV-1 Tax/HLA-A*0201 tetramer and an HTLV-1 Tax/HLA-A*2402 tetramer. Interestingly, the percentage of HTLV-1 Tax301-309/HLA-A*2402 tetramer(+)CD8(+) cells expressing PD-1 in ACs was significantly higher than the percentage of HTLV-1 Tax11-19/HLA-A*0201 tetramer(+)CD8(+) cells expressing PD-1. PD-1 expression was significantly downregulated on HTLV-1-specific CTLs in HAM/TSP compared with ACs. PD-L1 expression was observed in a small proportion of unstimulated lymphocytes from ACs and was greater in ACs than in HAM/TSP and CAIDs after short-term culture. Furthermore, CTL degranulation was impaired in HAM/TSP, whereas anti-PD-L1 blockade significantly increased CTL function in ACs. Downregulation of PD-1 on HTLV-1-specific CTLs and loss of PD-L1 expression in HAM/TSP and CAIDs, along with impaired function of HTLV-1-specific CTLs in HAM/TSP, may underlie the apparently dysfunctional immune response against HTLV-1., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Human T-lymphotropic virus type 1 (HTLV-1) is a type C retrovirus primarily endemic to Japan, Central and South America, the Middle East, regions of Africa, and the Caribbean. Currently, an estimated 10-20 million people worldwide are infected with this virus. Although the majority of infected individuals remain asymptomatic, HTLV-1 is the causative agent of a number of disorders, notably adult T-cell leukemia/lymphoma (ATLL) and a progressive demyelinating neurological disorder, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In addition to ATLL and HAM/TSP, HTLV-1 has been associated with a spectrum of skin disorders, such as infective dermatitis associated with HTLV-1, crusted scabies, and leprosy. The understanding of the interaction between virus and host response has improved markedly, but there are still few treatment options., (© 2011 The International Society of Dermatology.)

Adult T-cell leukemia/lymphoma is a distinct clinical entity characterized by a clonal proliferation of malignant T-lymphocytes. The etiologic agent of the disease is a Human T-cell lymphotropic virus type I. It occurs almost exclusively in areas where the virus is endemic; however the disease develops only in the minority of patients who are virus carriers. Karyotyping findings and their correlation with clinical features are still limited in T-cell malignancies, complicated by clinical heterogeneity and a plethora of secondary abnormalities. This study describes detailed chromosomal and fluorescence in situ hybridization results observed in a patient with adult T-cell leukemia/lymphoma and correlates them with clinical characteristics., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Lymphocytes of human T-lymphotropic virus type-I (HTLV-I) infected patients were previously found tolerant to mitogenic stimuli as well as glucocorticoid treatment. These data suggest that common signaling events are impaired during this infection. The underlying mechanisms of these phenomena may include changes in cellular composition, cytokine milieu and the differential activation of mitogen-activated protein kinases (MAPKs). We investigated the role of (i) p38 and ERK MAPKs, (ii) lymphocyte subpopulations, (iii) and cytokines implicated in antigen or glucocorticoid-induced immunomodulation. Twenty-one asymptomatic carriers (AC), 19 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 21 healthy subjects took part in this study. Lymphocytes were isolated and cultured in vitro to assess lymphocyte proliferation and sensitivity to dexamethasone. The expression of phospho-MAPKs, lymphocyte subsets and cytokines were assessed by flow cytometry. Patients with HAM/TSP had a higher p38/ERK ratio (p<0.05) associated with a reduced response to mitogens (phytohaemagglutinin or PMA+ionomycin) (p<0.001) and higher sensitivity to dexamethasone (p<0.05). HAM/TSP patients presented increased frequency of activated T cells and CD8(+)CD28(-) regulatory T cells, being negatively related to the mitogenic response. These data suggest that multiple underlying mechanisms could be involved with HTLV-related changes in cellular response to mitogens and glucocorticoids.

Human T lymphotropic virus type 1 is associated with some neurologic diseases, mainly human T lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis. Human T lymphotropic virus type 2 has also been associated with similar cases of human T lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis, but evidences for a definitive relationship are less clear. On the other hand, neurologic manifestations of HIV infection are quite common, affecting more than one third of patients in HIV clinics. Seroepidemiologic studies show that HIV-infected individuals are at an increased risk for human T lymphotropic virus infection and vice versa in comparison with the general population. Furthermore, HIV/human T lymphotropic virus coinfection has been associated with distinctive immunophenotypes and an increased risk for development of neurodegenerative conditions. Thus, studies on HIV/human T lymphotropic virus coinfection have a practice clinical importance. In this review, we aim to discuss clinical and laboratorial data focusing on neurologic diseases in HIV/human T lymphotropic virus coinfection.

Introduction: Human T-cell lymphotropic virus type-I (HTLV-I) causes tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM). Immunopathogenesis and available treatments for TSP/HAM are reviewed., Development: At least 20 million people are infected worldwide and 0.3-4% will develop TSP/HAM. Incidence in endemic areas is around 2 cases/ 100,000 inhabitants and year. The 50% of TSP/HAM patients suffer from clinical progression during their first ten years. Progression is associated with high proviral load and ager than 50 years at onset. HTLV-I proviral DNA and m-RNA load are significantly raised in TSP/HAM patients compared to asymptomatic carriers. This antigenic load activates T cells CD8+ specific for Tax-protein, which up-regulate pro-inflammatory cytokines. Corticoids, plasma-exchange, intravenous immunoglobulins, danazol, pentoxifilline, green-tea polyphenols, lactobacillus fermented milk, zidovudine, lamivudine, monoclonal antibodies (daclizumab), interferon, and valproic acid have been used in open trials in a small number of patients. Nevertheless, their clinical efficacy is limited. Interferon alpha and beta-1a have cytostatic properties and may cause a reduction in HTLV-I proviral load., Conclusions: High HTLV-I proviral load and an exaggerated pro-inflammatory cellular response are involved in the pathogenesis of TSP/HAM. No therapy has been conclusively shown to alter long-term disability associated with TSP/HAM. Multicentric clinical trials are necessary to assess long-term efficacy of interferon in TSP/HAM.

Adult T-cell leukemia/lymphoma (ATLL) is a rare malignancy caused by human T-cell leukemia virus-1. ATLL is endemic to Japan, and to date, there are only four case reports of patients from Romania who have developed ATLL. Here, we describe a woman living in Madison, Wisconsin, originally from Romania, who presented with an atypical papulosquamous eruption and was ultimately diagnosed with smoldering ATLL. Narrow-band ultraviolet-B (UV-B) therapy and mid-potency topical steroids resulted in skin clearing for approximately 5 months after diagnosis; however, she subsequently relapsed with disease refractory to both narrow band UV-B and psoralen plus ultraviolet A (PUV-A), progressed to acute ATLL and expired secondary to complications., (Copyright Blackwell Munksgaard 2008.)

The Tax1 oncoprotein encoded by Human T-lymphotropic virus type I is a major determinant of viral persistence and pathogenesis. Tax1 affects a wide variety of cellular signalling pathways leading to transcriptional activation, proliferation and ultimately transformation. To carry out these functions, Tax1 interacts with and modulates activity of a number of cellular proteins. In this review, we summarize the present knowledge of the Tax1 interactome and propose a rationale for the broad range of cellular proteins identified so far.

Human T-cell leukemia virus type 1 (HTLV-1) spreads through cell-to-cell contact by forming a virological synapse. Based on the finding that HTLV-1 envelope glycoprotein (Env) binds to a PDZ domain containing scaffold protein Dlg1, whose function has been implicated in the organization of neuronal and immunological synapses, we examined the role of Dlg1 in the cell-cell infection by HTLV-1. The coculture of an HTLV-1-infected T-cell line MT-2 with an uninfected MOLT-4 induced syncytium, a marker of cell-cell HTLV-1 infection, but an RNA interference-mediated knockdown of Dlg1 in both cells cooperatively reduced the syncytium formation. In HTLV-1-uninfected 293T cells, Dlg1 induced the clustering of GLUT1, a cellular receptor for HTLV-1, but such clustering was abrogated by a deletion of the PDZ domain binding motif of GLUT1 (GLUT1DeltaC). GLUT1 expression in MDBK cells induced HTLV-1-mediated syncytium formation, and the activity was much greater than that of GLUT1DeltaC. These results suggest that Dlg1, through the interaction with GLUT1 as well as Env, plays a positive role in the syncytium formation induced by HTLV-1.

Study Design: Cross-seccional analysis., Objective: To define the clinical usefulness of vestibular-evoked myogenic potential (VEMP) in detecting cervical medullar involvement related to human T-cell lymphotropic virus type 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP)., Summary of Background Data: VEMP is generated by acoustic or galvanic stimuli, passing through the vestibulo-spinal motor tract, the spinal nerves and recorded by means of surface electrodes on the sternocleidomastoid muscle. HAM/TSP is a progressive inflammatory myelopathy with predominant lesions at the thoracic spinal cord level, although the cervical spine can be affected. VEMP may be of value to investigate cervical myelopathy., Methods: Seventy-two individuals were evaluated of whom 30 HTLV-1 were seronegative and 42 HTLV-1 seropositive (22 asymptomatic, 10 with complaints of walking difficulty without definite HAM/TSP and 10 with definite HAM/TSP). VEMP was recorded using monaural delivered short tone burst (linear rise-fall 1 millisecond, plateau 2 milliseconds, 1 KHz) 118 dB NA, stimulation rate of 5 Hz, analysis time of 60 milliseconds, 200 stimuli, band pass filtered between 10 and 1.500 Hz., Results: VEMP was normal in the seronegative group (30 controls). In the seropositive, abnormal VEMP was seen in 11 of 22 (50%) of the HTLV-1 asymptomatic carriers, in 7 of 10 (70%) of those with complaints of walking difficulty and in 8 of 10 (80%) of the HAM/TSP patients. In this last group, the pattern of response was different. No VEMP response was more frequent when compared with the HTLV-1 asymptomatic group (2-tailed P-value = 0.001)., Conclusion: VEMP may possibly be useful to identify patients with cervical myelopathy and to distinguish variable degrees of functional damage. Minor injury would be related to latency prolongation and major injury to no potential-evoked response.

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.

Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor kappaB (NF-kappaB). NF-kappaB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-kappaB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1 alpha expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy.

Background: The HTLV-I oncoprotein, Tax, is a pleiotropic protein whose activity is partially regulated by its ability to interact with, and perturb the functions of, numerous cellular proteins. Tax is predominantly a nuclear protein that localizes to nuclear foci known as Tax Speckled Structures (TSS). We recently reported that the localization of Tax and its interactions with cellular proteins are altered in response to various forms of genotoxic and cellular stress. The level of cytoplasmic Tax increases in response to stress and this relocalization depends upon the interaction of Tax with CRM1. Cellular pathways and signals that regulate the subcellular localization of Tax remain to be determined. However, post-translational modifications including sumoylation and ubiquitination are known to influence the subcellular localization of Tax and its interactions with cellular proteins. The sumoylated form of Tax exists predominantly in the nucleus while ubiquitinated Tax exists predominantly in the cytoplasm. Therefore, we hypothesized that post-translational modifications of Tax that occur in response to DNA damage regulate the localization of Tax and its interactions with cellular proteins., Results: We found a significant increase in mono-ubiquitination of Tax in response to UV irradiation. Mutation of specific lysine residues (K280 and K284) within Tax inhibited DNA damage-induced ubiquitination. In contrast to wild-type Tax, which undergoes transient nucleocytoplasmic shuttling in response to DNA damage, the K280 and K284 mutants were retained in nuclear foci following UV irradiation and remained co-localized with the cellular TSS protein, sc35., Conclusion: This study demonstrates that the localization of Tax, and its interactions with cellular proteins, are dynamic following DNA damage and depend on the post-translational modification status of Tax. Specifically, DNA damage induces the ubiquitination of Tax at K280 and K284. Ubiquitination of these residues facilitates the dissociation of Tax from sc35-containing nuclear foci, and stimulates nuclear export of Tax through the CRM1 pathway.

Adult T-cell leukemia/lymphoma (ATLL) is a human malignancy associated with human T-cell leukemia virus type 1 (HTLV-1). The pathological features of the lymph nodes of ATLL change from those of lymphadenitis to Hodgkin's-like features and those of lymphoma. Chemokines and their receptors are closely associated with T-cell subgroups and immune responses. To clarify the relationship between chemokines and their receptor expression, as well as the development of ATLL, 17 cases with ATLL were analyzed using DNA chips of chemokines and their receptors. All cases showed a varied and mixed pattern of upregulated and downregulated gene expression of Th1, Th2, naïve, and cytotoxic cell-associated chemokine genes. As CC chemokine ligand 18 (CCL18) accounted for the most upregulated gene and CX3C chemokine receptor 1 (CX3CR1) for the most downregulated gene, they were selected for immunohistochemical analysis. Immunohistochemical staining showed expression of the two genes in immunological cells, with a positive expression for reticulum cells, but not for ATLL cells. HTLV-1-associated lymphadenitis type (n = 13) and Hodgkin's-like type (n = 12) cases showed significantly higher CCL18 expression than the non-specific lymphadenitis cases (n = 10) (P < 0.05). However, all HTLV-1-associated cases showed significantly lower CX3CR1 expression than the non-specific lymphadenitis cases (P < 0.05). These results suggest that upregulation of CCL18 expression and downregulation of CX3CR1 expression play a role in immune responses against the ATLL cells.

Objective: Human T lymphotropic virus type I (HTLV-I) may be associated with some connective tissue autoimmune diseases, including systemic lupus erythematosus (SLE). To determine the relationship between HTLV-I infection and SLE, we examined the clinical manifestations of SLE patients with HTLV-I infection., Methods: Eighty-nine patients with SLE were screened for antibodies to HTLV-I by electrochemiluminescence immunoassay. The presence of HTLV-I proviral sequences in peripheral blood mononuclear cells (PBMC) was determined by real-time polymerase chain reaction (PCR) quantification and Southern blotting analysis. The differences in clinical manifestations between HTLV-I-seropositive and seronegative patients with SLE were analyzed statistically., Results: Fourteen of 89 (15.7%) patients were HTLV-I seropositive. All PBMC samples from 11 patients tested by PCR and 3 samples from 10 patients tested by Southern blotting analysis were positive for HTLV-I-related sequences. The age of HTLV-I-seropositive patients with SLE was significantly higher than that of seronegative patients (median 60 vs 42 yrs; p < 0.0005). The age at onset of SLE in HTLV-I-seropositive patients was also significantly higher than that of seronegative patients (median 45.5 vs 30 yrs; p <0.0005). The lymphocyte count in HTLV-I-seropositive SLE patients was significantly higher than that of seronegative patients (median 1740 vs 1066/microl; p = 0.027). The maintenance dose of prednisolone in HTLV-I-seropositive patients with SLE was significantly lower than that in seronegative patients (median 5 vs 9 mg/day; p = 0.012)., Conclusion: This is the first report of the differences in clinical manifestations between SLE patients with and without HTLV-I infection. Our results suggest some involvement of HTLV-I in the pathogenesis of SLE.

We report a patient who experienced progressive diplopia and distal weakness of the upper limbs. Magnetic resonance imaging of the brain showed extensive white matter lesions and analysis of cerebrospinal fluid revealed acute human T-lymphotropic virus type I (HTLV-I) infection. Myasthenia gravis (MG) was evidenced by electromyography (EMG) and antibodies against acetylcholine receptor. This unusual case of MG associated with HTLV-I infection and brain-restricted lesions underscores the possible link between viruses and MG pathogenesis.

Adult T-cell leukemia/lymphoma (ATLL) is a malignancy slowly emerging from human T-cell leukemia virus type 1 (HTLV-I)-infected mature CD4(+) T-cells. To characterize the molecular modifications induced by HTLV-I infection, we compared HTLV-I-infected WE17/10 cells with control cells, using micro-arrays. Many calcium-related genes were progressively downmodulated over a period of 2 years. Infected cells acquired a profound decrease of intracellular calcium levels in response to ionomycin, timely correlated with decreased CD7 expression. Focusing on apoptosis-related genes and their relationship with CD7, we observed an underexpression of most antiapoptotic genes. Western blotting revealed increasing Akt and Bad phosphorylation, timely correlated with CD7 loss. This was shown to be phosphatidylinositol 3-kinase (PI3K)-dependent. Activation of PI3K/Akt induced resistance to the apoptotic effect of interleukin-2 deprivation. We thus propose the following model: HTLV-I infection induces a progressive decrease in CD3 genes expression, which eventually abrogates CD3 expression; loss of CD3 is known to perturb calcium transport. This perturbation correlates with loss of CD7 expression and induction of Akt and Bad phosphorylation via activation of PI3K. The activation of the Akt/Bad pathway generates a progressive resistance to apoptosis, at a time HTLV-I genes expression is silenced, thus avoiding immune surveillance. This could be a major event in the process of the malignant transformation into ATLL.