Human T Lymphotropic Virus Type 1 (HTLV-1) Proviral Load in Asymptomatic Carriers, HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis, and Other Neurological Abnormalities Associated with HTLV-1 Infection
M.T.T. SilvaR. C. HarabAna Claúdia Celestino Bezerra LeiteDoris SchorAbelardo AraújoMaria J. Andrada‐Serpa
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Abstract:
Recent reports have demonstrated that human T lymphotropic virus type 1 (HTLV-1) is associated with other neurological abnormalities in addition to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It has been well established that high HTLV-1 proviral loads are associated with the development of HAM/TSP. We now demonstrate, for the first time, to our knowledge, that HTLV-1 proviral loads in patients with other neurological abnormalities are also significantly higher than in asymptomatic HTLV-1 carriers.Keywords:
Tropical spastic paraparesis
Human T-lymphotropic virus
Asymptomatic carrier
Human T-lymphotropic virus type-1 (HTLV-1) infection was diagnosed in a Thai patient with chronic progressive myelopathy. The phylogenetic tree of the ltr sequencing of HTLV-1 indicated that the virus belongs to the transcontinental genotype of the cosmopolitan subtype A. This is the first case report of HTLV-1-associated myelopathy in Southeast Asia. Awareness of HTLV-1 and related condition should be encouraged in this region and routine screening should be applied to blood donors.
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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.
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Recent reports have demonstrated that human T lymphotropic virus type 1 (HTLV-1) is associated with other neurological abnormalities in addition to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It has been well established that high HTLV-1 proviral loads are associated with the development of HAM/TSP. We now demonstrate, for the first time, to our knowledge, that HTLV-1 proviral loads in patients with other neurological abnormalities are also significantly higher than in asymptomatic HTLV-1 carriers.
Tropical spastic paraparesis
Human T-lymphotropic virus
Asymptomatic carrier
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Tropical spastic paraparesis
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Asymptomatic carrier
Human T-lymphotropic virus
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Tropical spastic paraparesis
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Human T-lymphotropic Virus type 1 (HTLV-1) is associated with a myelopathy (namedHTLV-associated myelopathy/Tropical Spastic Paraparesis–HAM/TSP). Thrombospondin-1 (TSP-1) is a matrix protein which interferes with cell adhesion, motility, and proliferation. The expression levels of the mRNA for this protein were evaluated in HTLV-1 infected individuals: 11 asymptomatic, 18 with myelopathy or oligosymptomatic, and 13 non-infected participants. RNA from peripheral blood mononuclear cells was submitted to TSP-1 RT-PCR analysis. The number of individuals expressing thrombospondin-1 was more frequent in the symptomatic group (14/18, p=0.007). In general, a tendency to higher values of the protein´s mRNA was observed in the HTLV-1-infected group (p=0.062). The highest mRNA TSP-1 expression levels were detected at the beginning of the clinical symptoms of myelopathy. Additional studies with larger sample sizes are deemed to further elucidate the role of this matrix protein in the inflammatory network related to the HTLV-associated myelopathy/Tropical Spastic Paraparesis.
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The aim of this study is to identify HTLV-1 minor strains that change the bind sites for transcriptional factors in the LTR promoter region. For this purpose 28 patients samples were analyzed, being 14 with TSP/HAM and 14 health carriers. The LTR fragments were submitted to the deep sequencing using the Ion Torrent methodology for a 200bp read in a 314 chip. We found 172 variations in these 28 patients samples. The single nucleotide polymorphisms (SNP) screening showed minor variants strains in the previously described transcriptional factor bind sites (TxRE-2 and 3, ETS binding sites and SP1 binding sites). In addition a SNP in the TATA box from an asymptomatic carrier sample was found in 90% of the sequences changing the site from TATAAA to TCTAAA (depth of 2632 nucleotides). Two asymptomatic carriers samples showed a 9 and 11 base pair deletion in all the sequences, being the 9 base pair deletion between the first and second TxRE and the 11 base pair deletion in the second TxRE. The number of minor variants was not constant (0 to 19) and was not related to proviral load or clinical status. An in silico analyze has being done in order to identify the motifs for transcriptional bind factor in those minor variants. The site directed mutagenesis followed by a luciferase assay will be performed to analyze the LTR activation in those strains.
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Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is associated with accumulation of HTLV-I-infected T cells in the central nervous system (CNS). However, data on HTLV-I proviral load in the CNS at the asymptomatic stage are still lacking. We measured HTLV-I proviral load in cerebrospinal fluid (CSF) cells from 17 patients with HAM/TSP and 25 asymptomatic carriers. The percentage of HTLV-I-infected cells in CSF cells and the CSF cell : peripheral blood mononuclear cell HTLV-I proviral load ratio were always >10% and >1, respectively, in the patients with HAM/TSP but were always <10% and <1, respectively, in the asymptomatic carriers. We propose that determination of HTLV-I proviral load in CSF cells should be included as a new parameter for the diagnosis of HAM/TSP.
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We conducted a prospective clinical and epidemiologic evaluation of 45 cases of human T lymphotropic virus type I (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in São Paulo, Brazil. All enrolled patients had progressive chronic myelopathy and high titers of HTLV-I and HTLV-II antibodies, as determined by enzyme immunoassay and western blot. In 24 cases, the polymerase chain reaction (PCR) was performed so that HTLV-I could be distinguished from HLTV-II. The clinical and epidemiologic features of the patients from our study were similar to those of patients with HAM/TSP from other areas of endemicity for HTLV-I except that more patients in our study had received a blood transfusion prior to their illness. Despite the presence of HTLV-II virus in Brazil, all patients whose serum was tested by PCR were found to be infected with the HTLV-I virus.
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We used in situ hybridization combined with immunocytochemistry, cell sorting, and the polymerase chain reaction (PCR) to investigate clinical events in three asymptomatic carriers of human T lymphotrophic virus type-1 (HTLV-1) and ten patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The objective was to determine which T cell subset of peripheral blood mononuclear cells (PBMC), CD4 or CD8, were infected by HTLV-1 and the manner in which HTLV-1 proviral DNA was expressed at the level of the single cell. Both CD4-positive and CD8-positive cells of the PBMC from five patients with HAM/TSP were infected with HTLV-1. The proportion of HTLV-1-infected cells was 2.5-40% in the CD4-positive subset and 1.0-65% in the CD8- positive subset, when quantified by PCR using HTLV-1-infected MT2 cells as a positive standard. Proviral DNA of HTLV-1 was expressed in both CD4-positive cells and CD8-positive cells of the PBMC from six patients with HAM/TSP and three asymptomatic HTLV-1 carriers. In patients with HAM/TSP, the proportion of the cells expressing HTLV-1 proviral DNA was 0.02-0.1% in both subsets. In asymptomatic carriers, the expression of HTLV-1 proviral DNA was 0.01-0.02% in the CD4-positive subset and 0.01% in the CD8-positive subset. Therefore, HTLV-1 possessed similar in vivo cellular tropism for both CD4-positive cells and CD8-positive cells and HTLV-1 proviral DNA was expressed in vivo in both circulating T cell subsets.(ABSTRACT TRUNCATED AT 250 WORDS)
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