Differentiation of HAM/TSP from patients with multiple sclerosis infected with HTLV-I

Neurological Service, Gaffree Guinle University Hospital, Federal University of Rio de Janeiro State, Rio de Janeiro, Brazil.
Neurology (Impact Factor: 8.29). 02/2007; 68(3):206-13. DOI: 10.1212/01.wnl.0000251300.24540.c4
Source: PubMed

ABSTRACT To better differentiate patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) from patients with multiple sclerosis (MS) who are HTLV-I seropositive, we compared the HTLV-I antibodies and HTLV-I proviral DNA loads in CSF and peripheral blood mononuclear cells (PBMC).
Intrathecal synthesis of HTLV-I antibodies and HTLV-I proviral DNA loads in CSF and PBMC were measured and compared in 39 Brazilian patients: 17 HAM/TSP and 22 HTLV-I-seropositive non-HAM/TSP (7 with other neurologic diseases, 11 asymptomatic carriers, and 4 HTLV-I-seropositive patients with an MS-like phenotype). In addition, we followed immunologic and virologic markers in comparison to the clinical course (by Kurtzke Expanded Disability Status Scale) of seven patients (five with HAM/TSP and two with an MS-like phenotype) for a mean period of 16 (SD +/- 5) months.
The proviral load in CSF and PBMC was higher in HAM/TSP than in non-HAM/TSP patients, except in the two HTLV-I-seropositive patients with an MS-like phenotype that also fulfilled the criteria for HAM/TSP. Higher HTLV-I proviral DNA load in CSF was associated with the higher proviral DNA load in PBMC and lower intrathecal synthesis of HTLV-I antibodies. These laboratory findings remained stable during follow-up.
The high proviral load in peripheral blood mononuclear cells or in CSF or both may be a good marker of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and can differentiate patients with HAM/TSP from patients with multiple sclerosis infected with HTLV-I.

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    • "Due to the high sensitivity and specificity and the ability to differentiate between specific viral proteins, the WB test can be valuable for assessing the intrathecal synthesis of anti-HTLV-1 Abs. In endemic areas, the use of a sensitive and specific biomarker may clarify the HAM/TSP diagnosis in mono or oligosymptomatic patients (Puccioni-Sohler et al. 2007, Slater et al. 2012). The aim of this study was to standardise the WB test (using paired CSF and serum samples) to detect specific intrathecal Abs for HAM/TSP diagnosis. "
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    ABSTRACT: Intrathecal synthesis of human T-lymphotropic virus type 1 (HTLV-1) antibodies (Abs) represents conclusive evidence of a specific immune response in the central nervous system of HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients. Western blotting (WB) for HTLV Abs in serum is a confirmatory test for HTLV-1 infection. The aim of this study was to standardise the Western blot to demonstrate the intrathecal pattern of Abs against HTLV-1 proteins in HAM/TSP patients. Paired cerebrospinal fluid (CSF) and serum samples were selected from 20 patients with definite HAM/TSP, 19 HTLV-1 seronegative patients and two HTLV-1 patients without definite HAM/TSP. The presence of reactive bands of greater intensity in the CSF compared to serum (or bands in only the CSF) indicated the intrathecal synthesis of anti-HTLV-1 Abs. All definite HAM/TSP patients presented with an intrathecal synthesis of anti-HTLV-1 Abs; these Abs were not detected in the control patients. The most frequent intrathecal targets of anti-HTLV-1 Abs were GD21, rgp46-I and p24 and, to a lesser extent, p19, p26, p28, p32, p36, p53 gp21 and gp46. The intrathecal immune response against env (GD21 and rgp46-I) and gag (p24) proteins represents the most important humoral pattern in HAM/TSP. This response may be used as a diagnostic marker, considering the frequent association of intrathecal anti-HTLV-1 Ab synthesis with HAM/TSP and the pathogenesis of this neurological disease.
    Memórias do Instituto Oswaldo Cruz 09/2013; 108(6):730-4. DOI:10.1590/0074-0276108062013009 · 1.59 Impact Factor
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    • "These results suggest that HBZ-specific antibody in the CSF is derived from the blood while antibodies for HTLV-1 Gag, Env and Tax are intrathecally synthesized. It has been previously reported that intrathecal antiviral antibody synthesis was confirmed by the presence of HTLV-1-specific antibodies and oligoclonal IgG in CSF [42-45] and that the lack of intrathecal antibody response to HTLV-1 in HAM/TSP correlates with higher proviral loads and worse outcome [46]. In the future it will be interesting to examine the relationship between CSF proviral load, and the presence or level of anti-HBZ antibody in CSF and to compare the clinical phenotype of HAM/TSP patients with and without CSF anti-HBZ antibodies. "
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    ABSTRACT: Human T cell lymphotropic virus type 1 (HTLV-1) infection can lead to development of adult T cell leukemia/lymphoma (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. HTLV-1 basic leucine zipper factor (HBZ) gene has a critical role in HTLV-1 infectivity and the development of ATL and HAM/TSP. However, little is known about the immune response against HBZ in HTLV-1-infected individuals. In this study, we examined antibody responses against HBZ in serum/plasma samples from 436 subjects including HTLV-1 seronegative donors, asymptomatic carriers (AC), ATL, and HAM/TSP patients using the luciferase immunoprecipitation system. Immunoreactivity against HBZ was detected in subsets of all HTLV-1-infected individuals but the test did not discriminate between AC, ATL and HAM/TSP. However, the frequency of detection of HBZ-specific antibodies in the serum of ATL patients with the chronic subtype was higher than in ATL patients with the lymphomatous subtype. Antibody responses against HBZ were also detected in cerebrospinal fluid of HAM/TSP patients with anti-HBZ in serum. Antibody responses against HBZ did not correlate with proviral load and HBZ mRNA expression in HAM/TSP patients, but the presence of an HBZ-specific response was associated with reduced CD4+ T cell activation in HAM/TSP patients. Moreover, HBZ-specific antibody inhibited lymphoproliferation in the PBMC of HAM/TSP patients. This is the first report demonstrating humoral immune response against HBZ associated with HTLV-I infection. Thus, a humoral immune response against HBZ might play a role in HTLV-1 infection.
    Retrovirology 02/2013; 10(Suppl 1):19. DOI:10.1186/1742-4690-10-19 · 4.19 Impact Factor
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    • "A recent study suggests that a high ratio of proviral DNA load in CSF to peripheral blood mononuclear cells (PBMCs) may distinguish HAM/TSP from HTLV-1-infected patients with MS (Puccioni-Sohler et al., 2007). In general, HTLV-1 proviral loads measured in the CSF of HAM/TSP patients are typically greater than twice the proviral load in PBMCs (Nagai et al., 2001; Takenouchi et al., 2003), whereas the ratio of CSF to peripheral blood HTLV-1 proviral loads are typically lower in asymptomatic carriers (Lezin et al., 2005; Puccioni-Sohler et al., 2007), reflecting either recruitment or expansion of HTLV-1-infected cells in the central nervous system (CNS). "
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    ABSTRACT: Human T-lymphotropic virus type 1 (HTLV-1), a human retrovirus, is the causative agent of a progressive neurological disease termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic inflammatory disease of the central nervous system and is characterized by unremitting myelopathic symptoms such as spastic paraparesis, lower limb sensory disturbance, and bladder/bowel dysfunction. Approximately 0.25-3.8% of HTLV-1-infected individuals develop HAM/TSP, which is more common in women than in men. Since the discovery of HAM/TSP, significant advances have been made with respect to elucidating the virological, molecular, and immunopathological mechanisms underlying this disease. These findings suggest that spinal cord invasion by HTLV-1-infected T cells triggers a strong virus-specific immune response and increases proinflammatory cytokine and chemokine production, leading to chronic lymphocytic inflammation and tissue damage in spinal cord lesions. However, little progress has been made in the development of an optimal treatment for HAM/TSP, more specifically in the identification of biomarkers for predicting disease progression and of molecular targets for novel therapeutic strategies targeting the underlying pathological mechanisms. This review summarizes current clinical and pathophysiological knowledge on HAM/TSP and discusses future focus areas for research on this disease.
    Frontiers in Microbiology 11/2012; 3:389. DOI:10.3389/fmicb.2012.00389 · 3.99 Impact Factor
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