Neurological aspects of HTLV-1 infection: symptoms in apparently asymptomatic carriers.

Human T-lymphotropic virus type 1 (HTLV-1) is classically associated with the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), although the mechanisms of this neurological disorder remain unclear. In addition, some patients who develop "minor" neurological signs that do not meet diagnostic criteria for HAM/TSP are classified as asymptomatic carriers. This study aims to demonstrate the neurological symptoms of Brazilian patients living with HTLV-1 classified as not-HAM.TSP. This observational study evaluated patients treated in an HTLV reference center in Bahia, Brazil, between February 2022 and July 2023. The data were obtained through the analysis of medical records and neurological consultation. Those individuals classified as HAM/ TSP were excluded from this study. 74 patients were submitted to a careful neurological evaluation: 23 HAM/TSP, 22 were classified with intermediate syndrome (IS), and 29 were oligosymptomatic. Self-reported symptoms were significantly more common in the IS group, including urinary symptoms such as nocturia, urgency, incontinence, dysuria, weakness, paresthesia, lumbar pain, xerostomia, and xerophthalmia. Physical examination findings consistent with reduced vibratory and tactile sensitivity were more common in the IS group (p = 0.017 and p = 0.013). Alterations in the V and VIII cranial nerves were present in both groups. HTLV-1 can lead to the development of important neurological signs and symptoms in apparently asymptomatic individuals. This data highlights the need for more research into the neurological aspects of HTLV-1 infection and emphasizes the importance of early diagnosis, treatment, and support for individuals living with this virus.

Ocular vestibular evoked myogenic potential (VEMP) reveals mesencephalic HTLV-1-associated neurological disease.

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.

Prevalence of Bowel Symptoms in Patients Infected with Human T-Lymphotropic type 1 Virus.

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.

Balance Impairments in Patients with Human T-Cell Lymphotropic Virus Type 1 Infection.

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.

Memory impairment: an intermediate clinical syndrome symptom in HTLV-1-infected 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.

Memory impairment: an intermediate clinical syndrome symptom in HTLV-1-infected patients? / Comprometimento da memória: um sintoma de síndrome clínica intermediária em pacientes infectados pelo HTLV-1?

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.

RESUMO Apesar da síndrome de HAM / TSP clássica ser a perturbação neurológica mais atribuída, alguns distúrbios neurológicos denominados "menores" são vistos em portadores "assintomáticos" de HTLV-1. Esses distúrbios, incluindo alterações cognitivas já observadas em descrições de casos clínicos e estudos, podendo constituir uma verdadeira síndrome clínica intermediária (SI) entre o estado assintomático e mielopatia. O objetivo deste estudo foi investigar a presença de déficits cognitivos em pacientes portadores do vírus HTLV-1 diagnosticados classicamente como assintomáticos. Métodos Foram avaliadas 54 pessoas, sendo 35 assintomáticos, 19 com alterações neurológicas menores (avaliados por um neurologista) e 25 HTLV-1 negativo. Os instrumentos utilizados foram: Inventário Beck de Depressão, Escala de Atividades de Vida Diária de Lawton e uma completa bateria neuropsicológica. A aplicação destes instrumentos de avaliação foi realizada de forma cega, ou seja, a avaliadora não sabia a condição clinica do paciente. Resultados A maioria dos participantes era do sexo feminino (n = 57, 72,21%), com idade média de 52.34 anos (DP = 14,29) e escolaridade média de 9.70 anos (DP = 4,11). Discussão Avaliando o desempenho cognitivo nos três grupos, foi possível observar que os participantes classificados com SI, apresentaram menores escores brutos, quando comparados, com os pacientes com classificação assintomática e grupo controle e, em relação à memória episódica auditiva de evocação imediata (p < 0,01) (p = 0,01) e tardia. Conclusão Diante dos resultados foi possível concluir que os pacientes com SI apresentam comprometimento de memória quando comparado com os outros grupos, sendo possível, ser este um dos sintomas para auxiliar na classificação da síndrome.

Prevalence of bowel symptoms in patients infected with human T-lymphotropic type 1 virus

Abstract 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.

Stability of the HTLV-1 glycoprotein 46 (gp46) gene in an endemic region of the Brazilian Amazon and the presence of a significant mutation (N93D) in symptomatic patients.

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.

CT Chest and pulmonary functional changes in patients with HTLV-associated myelopathy in the Eastern Brazilian Amazon.

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.

Quality of life and pain multidimensional aspects in individuals with HTLV-1.

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.

Barefoot Plantar Pressure Indicates Progressive Neurological Damage in Patients with Human T-Cell Lymphotropic Virus Type 1 Infection.

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.

HTLV-1 infects human mesenchymal stromal cell in vitro and modifies their phenotypic characteristics.

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.

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

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. .

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

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.

Correlation between LTR point mutations and proviral load levels among human T cell lymphotropic virus type 1 (HTLV-1) asymptomatic carriers.

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.

Changes in T cell phenotype and activated MAPKs are correlated to impaired cellular responses to antigens and glucocorticoids during HTLV-I infection.

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.

Neurological aspects of HIV/human T lymphotropic virus coinfection.

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.

[Immunopathogenesis and treatment of the myelopathy associated to the HTLV-I virus]. / Inmunopatogenesis y tratamiento de la mielopatia asociada al virus linfotropico humano de celulas T (HTLV-I).

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.

Vestibular-evoked myogenic potential (VEMP) to evaluate cervical myelopathy in human T-cell lymphotropic virus type I infection.

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.