HTLV1 proviral load in peripheral blood mononuclear cells quantified in 100 HAM/TSP patients: A marker of disease progression

Department of Neurology and UMR 433 INSERM, Pierre Zobda-Quitman Hospital, Fort-de-France, Martinique, French West Indies.
Journal of the Neurological Sciences (Impact Factor: 2.47). 10/2005; 237(1):53-59. DOI: 10.1016/j.jns.2005.05.010


A high proviral load of human T cell lymphotropic virus type 1 (HTLV-1) in peripheral blood mononuclear cells (PBMCs) has been reported in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The aim of the present study was to investigate the role of HTLV-1 proviral load in PBMCs (expressed as the number of copies per 106 PBMCs) in HAM/TSP disease course. One hundred consecutive HAM/TSP patients were recruited and assigned on the basis of the disability score and disease duration to either a rapid (n=38) or a slow (n=62) progression group. Thirty-four asymptomatic HTLV-1 carriers were also included. HTLV-1 proviral load was quantified in all HAM/TSP patients and asymptomatic subjects. The mean HTLV-1 proviral load was 6-fold lower in asymptomatic carriers than in HAM/TSP patients (18,224±24,811 vs. 107,905±96,651, p

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    • "HTLV-1 PVL is considered low if the proportion of infected PBMCs is lower than 1%, and high if greater than 5% [20]. High PVLs are commonly found in individuals with HAM/TSP [21, 22], infective dermatitis [23] and Keratoconjunctivitis sicca [24]. However, in some cases, asymptomatic individuals may have high PVLs and exhibit an exacerbated inflammatory response [14, 22]. "
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    ABSTRACT: Background: High HTLV-1 proviral load (PVL) is mainly found in infected individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However one third of asymptomatic carriers may have high PVL. This study aimed to evaluate the impact of PVL in the activation of T lymphocytes of asymptomatic individuals infected with HTLV-1. Methods: Membrane activation markers (CD25+, CD28+, CD45RO+, CD69+, CD62L+, HLA-DR+), FoxP3+ and intracellular IFN-γ expression were evaluated on both CD4+ and CD8+ T-lymphocytes from asymptomatic carriers with PVL ≥ and < 1% of infected cells, using flow cytometry. HTLV-1 proviral load was determined using real-time PCR. Results: Asymptomatic carriers with PVL ≥ 1% presented a higher frequency of CD4+CD25+CD45RO+ (13.2% vs. 4%, p = 0.02), CD4+HLA-DR+ (18% vs. 8.3%, p = 0.01) and CD4+IFN-γ+ (4.5%; 1%, p = 0.01) T-cells, than healthy donors. HTLV-1 PVL was directly correlated with the proportion of CD4+CD25+CD45RO+ T-cells (R = 0.7, p = 0.003). Moreover, a significant increase in the proportion of CD4 + FoxP3+ T-cells was observed in HTLV-1-infected individuals, compared to healthy donors. Conclusion: HTLV-1 PVL is associated with activation of both CD4+ and CD8+ T-lymphocytes in asymptomatic individuals. Prospective studies should be conducted to evaluate whether asymptomatic individuals with higher PVL and high immune activation are more prone to developing HTLV-1-associated diseases.
    BMC Infectious Diseases 08/2014; 14(1):453. DOI:10.1186/1471-2334-14-453 · 2.61 Impact Factor
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    • "The results of the present study are consistent with previous reports that HAM/TSP patients have significantly higher HTLV-1 PVL than AC or healthy controls in PBMC (Nagai et al. 1998; Olindo et al. 2005; Demontis et al. 2013), even though there were low numbers of AC in this report, a common limitation of studies performed in non-HTLV "
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    ABSTRACT: An elevated human T cell lymphotropic virus 1 (HTLV)-1 proviral load (PVL) is the main risk factor for developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-1 infected subjects, and a high cerebrospinal fluid (CSF) to peripheral blood mononuclear cell (PBMC) PVL ratio may be diagnostic of the condition. However, the standard method for quantification of HTLV-1 PVL-real-time PCR-has multiple limitations, including increased inter-assay variability in compartments with low cell numbers, such as CSF. Therefore, in this study, we evaluated a novel technique for HTVL-1 PVL quantification, digital droplet PCR (ddPCR). In ddPCR, PCR samples are partitioned into thousands of nanoliter-sized droplets, amplified on a thermocycler, and queried for fluorescent signal. Due to the high number of independent events (droplets), Poisson algorithms are used to determine absolute copy numbers independently of a standard curve, which enables highly precise quantitation. This assay has low intra-assay variability allowing for reliable PVL measurement in PBMC and CSF compartments of both asymptomatic carriers (AC) and HAM/TSP patients. It is also useful for HTLV-1-related clinical applications, such as longitudinal monitoring of PVL and identification of viral mutations within the region targeted by the primers and probe.
    Journal of NeuroVirology 04/2014; 20(4). DOI:10.1007/s13365-014-0249-3 · 2.60 Impact Factor
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    • "HAM/TSP is mainly a chronic inflammation of the white matter of the lower thoracic spinal cord, causing spastic paraparesis in the lower limbs [15]. Clinically, HAM/TSP is characterized by higher production of proinflammatory cytokines, such as interferon-γ and tumor necrosis factor-α (TNF-α), and accumulation of Tax-specific CD8+ T cells in the cerebrospinal fluid [16] [17] [18] [19] [20]. Patients with ATL frequently develop hypercalcemia. "
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    ABSTRACT: Human T-cell leukemia virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). Hypercalcemia is common in patients with ATL. These patients rarely develop metastatic calcification and acute pancreatitis. The underlying pathogenesis of this condition is osteoclast hyperactivity with associated overproduction of parathyroid hormone-related protein, which results in hypercalcemia in association with bone demineralization. The discovery of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL), its receptor RANK, and its decoy receptor osteoprotegerin (OPG), enhanced our understanding of the mechanisms of ATL-associated hypercalcemia. Macrophage inflammatory protein-1-α, tumor necrosis factor-α, interleukin-1, and interleukin-6 are important molecules that enhance the migration and differentiation of osteoclasts and the associated enhanced production of RANKL for osteoblast formation. In this paper, we focus on metastatic calcification and acute pancreatitis in ATL, highlighting recent advances in the understanding of the molecular role of the RANKL/RANK/OPG system including its interaction with various cytokines and calciotropic hormones in the regulation of osteoclastogenesis for bone resorption in hypercalcemic ATL patients.
    11/2012; 2012(3):128617. DOI:10.1155/2012/128617
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