Abstract
BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) -associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. Since the disease course of HAM/TSP varies among patients, there is a dire need for biomarkers capable of predicting the rate of disease progression. However, there have been no studies to date that have compared the prognostic values of multiple potential biomarkers for HAM/TSP.Methodology/Principal FindingsPeripheral blood and cerebrospinal fluid (CSF) samples from HAM/TSP patients and HTLV-1-infected control subjects were obtained and tested retrospectively for several potential biomarkers, including chemokines and other cytokines, and nine optimal candidates were selected based on receiver operating characteristic (ROC) analysis. Next, we evaluated the relationship between these candidates and the rate of disease progression in HAM/TSP patients, beginning with a first cohort of 30 patients (Training Set) and proceeding to a second cohort of 23 patients (Test Set). We defined “deteriorating HAM/TSP” as distinctly worsening function (≥3 grades on Osame's Motor Disability Score (OMDS)) over four years and “stable HAM/TSP” as unchanged or only slightly worsened function (1 grade on OMDS) over four years, and we compared the levels of the candidate biomarkers in patients divided into these two groups. The CSF levels of chemokine (C-X-C motif) ligand 10 (CXCL10), CXCL9, and neopterin were well-correlated with disease progression, better even than HTLV-1 proviral load in PBMCs. Importantly, these results were validated using the Test Set.Conclusions/SignificanceAs the CSF levels of CXCL10, CXCL9, and neopterin were the most strongly correlated with rate of disease progression, they represent the most viable candidates for HAM/TSP prognostic biomarkers. The identification of effective prognostic biomarkers could lead to earlier detection of high-risk patients, more patient-specific treatment options, and more productive clinical trials.
Highlights
Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus associated with persistent infection of T-cells [1]
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease caused by infection with human T-lymphotropic virus type 1 (HTLV1)
The proviral DNA load in peripheral blood mononuclear cells (PBMCs), serum soluble IL-2 receptor (sIL-2R), and plasma levels of the chemokines CXCL9, CXCL10, CXCL11, and CCL5 were measured in 22 asymptomatic carriers (ACs) and 30 HAM/TSP patients without any history of immunomodulating treatments, including corticosteroids, IFN-a, and immunosuppressive drugs
Summary
Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus associated with persistent infection of T-cells [1]. While the majority of HTLV-1-infected individuals remain asymptomatic, approximately 2.5–5% develop an aggressive T-cell malignancy, termed adult T-cell leukemia (ATL) [2,3] and 0.3–3.8% develop a serious chronic neuroinflammatory disease, termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [4,5,6]. Human T-lymphotropic virus type 1 (HTLV-1) -associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. Since the disease course of HAM/TSP varies among patients, there is a dire need for biomarkers capable of predicting the rate of disease progression. There have been no studies to date that have compared the prognostic values of multiple potential biomarkers for HAM/TSP
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