Comparison between the spastic paraplegia rating scale, Kurtzke scale, and Osame scale in the tropical spastic paraparesis/myelopathy associated with HTLV

INTRODUCTION:The objective of this study was to compare Osame's scale of motor incapacity and the expanded scale of the state of incapacity of Kurtzke with the spastic paraplegia rating scale for the clinical evaluation of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). METHODS: Patients with the diagnosis of infection by HTLV-I/HTLV-II and with the clinical suspicion of HAM/TSP were included in the study. RESULTS: There were 45 patients who were evaluated. When analyzing the results of the scales, the researchers found the following averages of 21.08 points for the spastic paraplegia rating scale, 4.35 points for Osame's scale, and 4.77 points for Kurtzke's scale. The relation between the scale of paraplegia with Osame's was very significant with p < 0.0001, and regarding Kurtzke's scale, there was a similar result of p < 0.0001. When comparing Osame's, Kurtze's, and the spastic paraplegia rating scale with the time of disease, the researchers found a significant result of p = 0.0004 for the scale of spastic paraplegia, p = 0.0018 for Osame's scale, and p < 0.0001 for Kurtzke's scale. CONCLUSION: The spastic paraplegia rating scale has a good relation with Osame's and Kurtzke's scales showing a p index that is very significant that indicates that, although the scale was not initially made to be applied to patients with HAM/TSP because of the infection by HLTV, it showed to be as efficient as Osame's and Kurtzke's scales in evaluating the patients' neurological conditions.

High HTLV-1 proviral load, a marker for HTLV-1 associated myelopathy/tropical spastic paraparesis, is also detected in patients with infective dermatitis associated with HTLV-1

Salvador (BA, Brazil) is an endemic area for human T-cell lymphotrophic virus type 1 (HTLV-1). The overall prevalence of HTLV-1 infection in the general population has been estimated to be 1.76%. HTLV-1 carriers may develop a variety of diseases such as adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and infective dermatitis associated with HTLV-1 (IDH). IDH is a chronic and severe form of childhood exudative and infective dermatitis involving mainly the scalp, neck and ears. It has recently been observed that 30% of patients with IDH develop juvenile HAM/TSP. The replication of HTLV-1 has been reported to be greater in adult HAM/TSP patients than in asymptomatic HTLV-1 carriers. In the current study, the proviral load of 28 children and adolescents with IDH not associated with HAM/TSP was determined and the results were compared to those obtained in 28 HTLV-1 adult carriers and 28 adult patients with HAM/TSP. The proviral load in IDH patients was similar to that of patients with HAM/TSP and much higher than that found in HTLV-1 carriers. The high levels of proviral load in IDH patients were not associated with age, duration of illness, duration of breast-feeding, or activity status of the skin disease. Since proviral load is associated with neurological disability, these data support the view that IDH patients are at high risk of developing HAM/TSP.

Lower numbers of circulating natural killer T (NK T) cells in individuals with human T lymphotropic virus type 1 (HTLV-1) associated neurological disease

Human T lymphotropic virus type 1 (HTLV-1) infects 10-20 million people worldwide. The majority of infected individuals are asymptomatic; however, approximately 3% develop the debilitating neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is also currently no cure, vaccine or effective therapy for HTLV-1 infection, and the mechanisms for progression to HAM/TSP remain unclear. NK T cells are an immunoregulatory T cell subset whose frequencies and effector functions are associated critically with immunity against infectious diseases. We hypothesized that NK T cells are associated with HAM/TSP progression. We measured NK T cell frequencies and absolute numbers in individuals with HAM/TSP infection from two cohorts on two continents: Sao Paulo, Brazil and San Francisco, CA, USA, and found significantly lower levels when compared with healthy subjects and/or asymptomatic carriers. Also, the circulating NK T cell compartment in HAM/TSP subjects is comprised of significantly more CD4(+) and fewer CD8(+) cells than healthy controls. These findings suggest that lower numbers of circulating NK T cells and enrichment of the CD4(+) NK T subset are associated with HTLV-1 disease progression.

INTERFERON BETA-1A TREATMENT IN HTLV-1-ASSOCIATED MYELOPATHY/TROPICAL SPASTIC PARAPARESIS: A CASE REPORT

Here a young patient (< 21 years of age) with a history of infective dermatitis is described. The patient was diagnosed with myelopathy associated with HTLV-1/tropical spastic paraparesis and treated with interferon beta-1a. The disease was clinically established as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and laboratory tests confirmed the presence of antibodies to HTLV-1 in the cerebrospinal fluid (CSF). Mumps, cytomegalovirus, Epstein-Barr virus, schistosomiasis, herpes virus 1 and 2, rubella, measles, varicella-zoster toxoplasmosis, hepatitis, HIV, and syphilis were excluded by serology. The patient was diagnosed with neurogenic bladder and presented with nocturia, urinary urgency, paresthesia of the lower left limb, a marked reduction of muscle strength in the lower limbs, and a slight reduction in upper limb strength. During the fourth week of treatment with interferon beta-1a, urinary urgency and paresthesia disappeared and clinical motor skills improved.

HTLV-1 associated myelopathy diagnosed during lepromatous leprosy reaction treatment: a case report

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

HTLV-I associated cutaneous T-cell lymphoma: report of a case with atypical clinical presentation

A case of a 20-years-old black man from Salvador, Bahia with HTLV-I associated T cell lymphoma is presented. In spite of the absence of splenomegaly and leukemia, the patient had a marked cephalic tumoral infiltrationassociated with axillary tumors in a pattern not yet described in adult T cell lymphoma. Peripheral blood involvement was observed later on in the course of thedisease. The patient underwent chemotherapy but died seven monts after diagnosis.

Upregulation of hsa-miR-125b in HTLV-1 asymptomatic carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis patients

The retrovirus human T lymphotropic virus type 1 (HTLV-1) promotes spastic paraparesis, adult T cell leukaemia and other diseases. Recently, some human microRNAs (miRNAs) have been described as important factors in host-virus interactions. This study compared miRNA expression in control individuals, asymptomatic HTLV-1 carriers and HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis patients. The proviral load and Tax protein expression were measured in order to characterize the patients. hsa-miR-125b expression was significantly higher in patients than in controls (p = 0.0285) or in the HAM group (p = 0.0312). Therefore, our findings suggest that miR-125b expression can be used to elucidate the mechanisms of viral replication and pathogenic processes.

HLA class I - associated immunodominance affects CTL responsiveness to an ESO recombinant protein tumor antigen vaccine.

PURPOSE: Vaccination with full-length human tumor antigens aims at inducing or increasing antitumor immune responses, including CD8 CTL in cancer patients across the HLA barrier. We have recently reported that vaccination with a recombinant tumor-specific NY-ESO-1 (ESO) protein, administered with Montanide and CpG resulted in the induction of specific integrated antibody and CD4 T cell responses in all vaccinated patients examined, and significant CTL responses in half of them. Vaccine-induced CTL mostly recognized a single immunodominant region (ESO 81-110). The purpose of the present study was to identify genetic factor(s) distinguishing CTL responders from nonresponders. EXPERIMENTAL DESIGN: We determined the HLA class I alleles expressed by CTL responders and nonresponders using high-resolution molecular typing. Using short overlapping peptides spanning the ESO immunodominant CTL region and HLA class I/ESO peptide tetramers, we determined the epitopes recognized by the majority of vaccine-induced CTL. RESULTS: CTL induced by vaccination with ESO protein mostly recognized distinct but closely overlapping epitopes restricted by a few frequently expressed HLA-B35 and HLA-Cw3 alleles. All CTL responders expressed at least one of the identified alleles, whereas none of the nonresponders expressed them. CONCLUSIONS: Expression of HLA-B35 and HLA-Cw3 is associated with the induction of immunodominant CTL responses following vaccination with recombinant ESO protein. Because recombinant tumor-specific proteins are presently among the most promising candidate anticancer vaccines, our findings indicate that the monitoring of cancer vaccine trials should systematically include the assessment of HLA association with responsiveness.

In vivo fluctuation of Tax, Foxp3, CTLA-4, and GITR mRNA expression in CD4+CD25+ T cells of patients with human T-lymphotropic virus type 1-associated myelopathy

HTLV-1 Tax expression exerts an inhibitory effect on the Foxp3 transcription factor in CD4+CD25+ T-regulatory cells (Treg). For a better understanding of the role of Tax mRNA in the gene expression of cellular markers we measured Tax, Foxp3, CTLA-4, GITR, TGF-β, and IL-10 mRNA in Treg cells of 50 patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP; 27 women and 23 men; mean age: 56.7 years). The control group consisted of 23 non-infected subjects (12 women and 11 men) with a mean age of 51.3 years. Real-time PCR was used to measure mRNA of Tax proteins and several cellular markers of Treg function. Determinations revealed a high level of Tax mRNA in HAM/TSP (124.35 copies/100 CD4+CD25+ T cells). Foxp3, GITR, and CTLA-4 mRNA levels were lower in HAM/TSP patients (mean ± SD, 22.07 ± 0.78, 9.63 ± 0.36, and 4.54 ± 0.39, respectively) than in non-infected controls (47.15 ± 12.94, 22.14 ± 1.91, and 21.07 ± 2.31). Both groups had similar levels of TGF-β and IL-10. An inverse relationship was found between Tax levels and Foxp3, CTLA-4, and GITR levels. Conversely, there was a direct correlation between levels of Foxp3, GITR, and CTLA-4. Disease severity and evolution time did not correlate with Tax or Foxp3 levels. The present results suggest that Tax and Foxp3 mRNA vary with the same degree of disease severity in HAM/TSP patients. Tax fluctuations may affect CTLA-4 and GITR expression via the Foxp3 pathway, causing virus-induced dysfunction of CD4+CD25+ T cells in HAM/TSP patients.

Landscape Genetics of Raccoons (Procyon lotor) Associated with Ridges and Valleys of Pennsylvania: Implications for Oral Rabies Vaccination Programs

Raccoons are the reservoir for the raccoon rabies virus variant in the United States. To combat this threat, oral rabies vaccination (ORV) programs are conducted in many eastern states. To aid in these efforts, the genetic structure of raccoons (Procyon lotor) was assessed in southwestern Pennsylvania to determine if select geographic features (i.e., ridges and valleys) serve as corridors or hindrances to raccoon gene flow (e.g., movement) and, therefore, rabies virus trafficking in this physiographic region. Raccoon DNA samples (n = 185) were collected from one ridge site and two adjacent valleys in southwestern Pennsylvania (Westmoreland, Cambria, Fayette, and Somerset counties). Raccoon genetic structure within and among these study sites was characterized at nine microsatellite loci. Results indicated that there was little population subdivision among any sites sampled. Furthermore, analyses using a model-based clustering approach indicated one essentially panmictic population was present among all the raccoons sampled over a reasonably broad geographic area (e.g., sites up to 36 km apart). However, a signature of isolation by distance was detected, suggesting that widths of ORV zones are critical for success. Combined, these data indicate that geographic features within this landscape influence raccoon gene flow only to a limited extent, suggesting that ridges of this physiographic system will not provide substantial long-term natural barriers to rabies virus trafficking. These results may be of value for future ORV efforts in Pennsylvania and other eastern states with similar landscapes.

Upregulation of hsa-miR-125b in HTLV-1 asymptomatic carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis patients

The retrovirus human T lymphotropic virus type 1 (HTLV-1) promotes spastic paraparesis, adult T cell leukaemia and other diseases. Recently, some human microRNAs (miRNAs) have been described as important factors in host-virus interactions. This study compared miRNA expression in control individuals, asymptomatic HTLV-1 carriers and HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis patients. The proviral load and Tax protein expression were measured in order to characterize the patients. hsa-miR-125b expression was significantly higher in patients than in controls (p = 0.0285) or in the HAM group (p = 0.0312). Therefore, our findings suggest that miR-125b expression can be used to elucidate the mechanisms of viral replication and pathogenic processes.

Aquaporin-4 Antibodies Are Not Related to HTLV-1 Associated Myelopathy

Introduction: The seroprevalence of human T-cell leukemia virus type 1 (HTLV-1) is very high among Brazilians (,1:200). HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP) is the most common neurological complication of HTLV-1 infection. HAM/TSP can present with an acute/subacute form of longitudinally extensive myelitis, which can be confused with lesions seen in aquaporin-4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorders (NMOSD) on MRI. Moreover, clinical attacks in patients with NMOSD have been shown to be preceded by viral infections in around 30% of cases. Objective: To evaluate the frequency of AQP4-Ab in patients with HAM/TSP. To evaluate the frequency of HTLV-1 infection in patients with NMOSD. Patients and Methods: 23 Brazilian patients with HAM/TSP, 20 asymptomatic HTLV-1+ serostatus patients, and 34 with NMOSD were tested for AQP4-Ab using a standardized recombinant cell based assay. In addition, all patients were tested for HTLV-1 by ELISA and Western blotting. Results: 20/34 NMOSD patients were positive for AQP4-Ab but none of the HAM/TSP patients and none of the asymptomatic HTLV-1 infected individuals. Conversely, all AQP4-Ab-positive NMOSD patients were negative for HTLV-1 antibodies. One patient with HAM/TSP developed optic neuritis in addition to subacute LETM; this patient was AQP4-Ab negative as well. Patients were found to be predominantly female and of African descent both in the NMOSD and in the HAM/TSP group; Osame scale and expanded disability status scale scores did not differ significantly between the two groups. Conclusions: Our results argue both against a role of antibodies to AQP4 in the pathogenesis of HAM/TSP and against an association between HTLV-1 infection and the development of AQP4-Ab. Moreover, the absence of HTLV-1 in all patients with NMOSD suggests that HTLV-1 is not a common trigger of acute attacks in patients with AQP4-Ab positive NMOSD in populations with high HTLV-1 seroprevalence.

Co-presentation of human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis and adult-onset infective dermatitis associated with HTLV-1 infection

Background  Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), infective dermatitis associated with HTLV-1 (IDH), and various other clinical conditions. Several of these diseases can occur in association. Objective  Report an association of diseases related to HTLV-1 infection, occurring in an unusual age group. Methods  Dermatological and laboratory exams were consecutively performed in HTLV-1-infected individuals from January 2008 to July 2010 in the HTLV Outpatient Clinic at the Institute of Infectious Diseases “Emilio Ribas” in São Paulo, Brazil. Results  A total of 193 individuals (73 HAM/TSP and 120 asymptomatic carriers) were evaluated, three of which were associated with adult-onset IDH and HAM/TSP. In all three cases, the patients were affected by IDH after the development and progression of HAM/TSP-associated symptoms. Limitations  Small number of cases because of the rarity of these diseases. Conclusion  We draw attention to the possibility of co-presentation of adult-onset IDH in patients with a previous diagnosis of HAM/TSP, although IDH is a disease classically described in children. Thus, dermatologists should be aware of these diagnoses in areas endemic for HTLV-1 infection.

Differential activation of proliferation and cytotoxicity in human T-cell lymphotropic virus type I Tax-specific CD8 T cells by an altered peptide ligand.

Human T-cell leukemia virus type I (HTLV-I) gives rise to a neurologic disease known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the pathogenesis of the disease is unknown, the presence of a remarkably high frequency of Tax-specific, cytotoxic CD8 T cells may suggest a role of these cells in the development of HAM/TSP. Antigen-mediated signaling in a CD8 T-cell clone specific for the Tax(11-19) peptide of HTLV-I was studied using analog peptides substituted in their T-cell receptor contact residues defined by x-ray crystallographic data of the Tax(11-19) peptide in the groove of HLA-A2. CD8 T-cell stimulation with the wild-type peptide antigen led to activation of p56lck kinase activity, interleukin 2 secretion, cytotoxicity, and clonal expansion. A Tax analog peptide with an alanine substitution of the T-cell receptor contact residue tyrosine-15 induced T-cell-mediated cytolysis without activation of interleukin 2 secretion or proliferation. Induction of p56lck kinase activity correlated with T-cell-mediated cytotoxicity, whereas interleukin 2 secretion correlated with [3H]thymidine incorporation and proliferation. Moreover, Tax peptide analogs that activated the tyrosine kinase activity of p56lck could induce unresponsiveness to secondary stimulation with the wild-type peptide. These observations show that a single amino acid substitution in a T-cell receptor contact residue of Tax can differentially signal CD8 T cells and further demonstrate that primary activation has functional consequences for the secondary response of at least some Tax-specific CD8 T cells to HTLV-I-infected target cells.