Publications (6)33.08 Total impact
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Article: Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes.
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ABSTRACT: A determinant of human T-lymphotropic virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) development is the HTLV-1-infected cell burden. Viral proteins Tax and HBZ, encoded by the sense and antisense strands of the pX region, respectively, play key roles in HTLV-1 persistence. Tax drives CD4(+)-T cell clonal expansion and is the immunodominant viral antigen recognized by the immune response. Valproate (2-n-propylpentanoic acid, VPA), a histone deacetylase inhibitor, was thought to trigger Tax expression, thereby exposing the latent HTLV-1 reservoir to immune destruction. We evaluated the impact of VPA on Tax, Gag, and HBZ expressions in cultured lymphocytes from HTLV-1 asymptomatic carriers and HAM/TSP patients. Approximately one-fifth of provirus-positive CD4(+) T cells spontaneously became Tax-positive, but this fraction rose to two-thirds of Tax-positive-infected cells when cultured with VPA. Valproate enhanced Gag-p19 release. Tax- and Gag-mRNA levels peaked spontaneously, before declining concomitantly to HBZ-mRNA increase. VPA enhanced and prolonged Tax-mRNA expression, whereas it blocked HBZ expression. Our findings suggest that, in addition to modulating Tax expression, another mechanism involving HBZ repression might determine the outcome of VPA treatment on HTLV-1-infected-cell proliferation and survival.Blood 04/2011; 118(9):2483-91. · 9.90 Impact Factor -
Article: HTLV-1 evades type I interferon antiviral signaling by inducing the suppressor of cytokine signaling 1 (SOCS1).
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ABSTRACT: Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of Adult T cell Leukemia (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the majority of HTLV-1-infected individuals remain asymptomatic carriers (AC) during their lifetime, 2-5% will develop either ATL or HAM/TSP, but never both. To better understand the gene expression changes in HTLV-1-associated diseases, we examined the mRNA profiles of CD4+ T cells isolated from 7 ATL, 12 HAM/TSP, 11 AC and 8 non-infected controls. Using genomic approaches followed by bioinformatic analysis, we identified gene expression pattern characteristic of HTLV-1 infected individuals and particular disease states. Of particular interest, the suppressor of cytokine signaling 1--SOCS1--was upregulated in HAM/TSP and AC patients but not in ATL. Moreover, SOCS1 was positively correlated with the expression of HTLV-1 mRNA in HAM/TSP patient samples. In primary PBMCs transfected with a HTLV-1 proviral clone and in HTLV-1-transformed MT-2 cells, HTLV-1 replication correlated with induction of SOCS1 and inhibition of IFN-α/β and IFN-stimulated gene expression. Targeting SOCS1 with siRNA restored type I IFN production and reduced HTLV-1 replication in MT-2 cells. Conversely, exogenous expression of SOCS1 resulted in enhanced HTLV-1 mRNA synthesis. In addition to inhibiting signaling downstream of the IFN receptor, SOCS1 inhibited IFN-β production by targeting IRF3 for ubiquitination and proteasomal degradation. These observations identify a novel SOCS1 driven mechanism of evasion of the type I IFN antiviral response against HTLV-1.PLoS Pathogens 01/2010; 6(11):e1001177. · 9.13 Impact Factor -
Article: HTLV-1 proviral load in peripheral blood mononuclear cells quantified in 100 HAM/TSP patients: a marker of disease progression.
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ABSTRACT: 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 10(6) 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<0.0001) and significantly higher in rapid progression patients than in slow progression patients (146,469+/-98,943 vs. 84,270+/-87,912, p=0.0002). HTLV-1 proviral load in HAM/TSP patients was independent of age at the time of study, age at onset, and disease duration, and was not related to ophthalmological-associated disease or Chisholm grade. A high level of pulmonary lymphocytosis correlated with high HTLV-1 proviral load level (p=0.01). Our results suggest that the level of HTLV-1 proviral load in PBMCs parallels the course of HTLV-1 infection, being low in asymptomatic carriers and high and very high, respectively, in slow and rapid progression HAM/TSP patients. The magnitude of the HTLV-1 proviral load in PBMCs can be used as a biological marker of disease progression and could be a useful marker of disease activity in the monitoring of therapeutic trials.Journal of the Neurological Sciences 11/2005; 237(1-2):53-9. · 2.35 Impact Factor -
Article: Increased proviral load in HTLV-1-infected patients with rheumatoid arthritis or connective tissue disease.
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ABSTRACT: Human T-lymphotropic virus type 1 (HTLV-1) proviral load is related to the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and has also been shown to be elevated in the peripheral blood in HTLV-1-infected patients with uveitis or alveolitis. Increased proliferation of HTLV-1-infected cells in, or migration of such cells into, the central nervous system is also seen in HAM/TSP. In the present study, we evaluated the proviral load in a cohort of HTLV-1-infected patients with arthritic conditions. HTLV-1 proviral load in the peripheral blood from 12 patients with RA and 6 patients with connective tissue disease was significantly higher than that in matched asymptomatic HTLV-1 carriers, but similar to that in matched HAM/TSP controls. HAM/TSP was seen in one-third of the HTLV-1-infected patients with RA or connective tissue disease, but did not account for the higher proviral load compared to the asymptomatic carrier group. The proviral load was increased in the synovial fluid and tissue from an HTLV-1-infected patient with RA, the values suggesting that the majority of infiltrated cells were HTLV-1-infected. In the peripheral blood from HTLV-1-infected patients with RA or connective tissue disease, HTLV-1 proviral load correlated with the percentages of memory CD4+ T cells and activated T cells, and these percentages were shown to be markedly higher in the synovial fluid than in the peripheral blood in an HTLV-1-infected patient with RA. These biological findings are consistent with a role of the retrovirus in the development of arthritis in HTLV-1-infected patients. A high level of HTLV-1-infected lymphocytes in the peripheral blood and their accumulation in situ might play a central role in the pathogenesis of HTLV-1-associated inflammatory disorders. Alternatively, the autoimmune arthritis, its etiological factors or treatments might secondarily enhance HTLV-1 proviral load.Retrovirology 02/2005; 2:4. · 6.47 Impact Factor -
Article: Evaluation of HTLV-I removal by filtration of blood cell components in a routine setting.
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ABSTRACT: WBC depletion by filtration may prevent the transmission of HTLV-I, which requires cell-to-cell contact. The removal of HTLV-I-infected cells in routinely filtered blood cell components was measured. The study was conducted in Martinique where systematic screening for HTLV-I and -II and universal leukoreduction are mandatory. HTLV-I was quantified by use of real-time PCR in 8 RBC units and 4 PLT concentrates before and after filtration. HTLV-I proviral load in PBMNCs was determined in five of the eight HTLV-I-infected blood donors. The amount of MNC-associated HTLV-I DNA in RBC units before filtration was 21 x 10(6)+/- 29 x 10(6) copies (mean +/- SD). HTLV-I was detected in 4 of 8 RBC units after filtration, with a number of copies in the MNC fraction ranging from 20 to 140, following a 4.9 to 5.8 log reduction. Flow cytometry analysis performed in 2 of the filtered RBC units containing detectable HTLV-I showed suboptimal and out-of-range leukoreduction (0.56 x 10(6) and 1.22 x 10(6) residual WBCs). HTLV was not detected in filtered RBCs from the blood donor with the highest percentage of HTLV-I-infected PBMCs (9%). This study confirms that HTLV-I-infected cells can be detected in filtered blood cell components and shows that optimal leukoreduction is critical for HTLV-I removal.Transfusion 02/2004; 44(1):42-8. · 3.22 Impact Factor -
Article: Quantitation of HTLV-I proviral load by a TaqMan real-time PCR assay.
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ABSTRACT: A quantitative real-time PCR assay was developed to measure the proviral load of human T-lymphotropic virus type I (HTLV-I) in peripheral blood mononuclear cells (PBMCs). The HTLV-I copy number was referred to the actual amount of cellular DNA by means of the quantitation of the albumin gene. Ten copies of HTLV-I DNA could be detected with 100% sensitivity, and the assay had a wide range of at least 5 log(10). Intra- and inter-assay reproducibility was evaluated using independent extractions of PBMCs from an HTLV-I-infected patient (coefficients of variation, 24 and 7% respectively). The performance of this TaqMan PCR assay, coupled with its high throughput, thus allows reliable routine follow-up of HTLV-I proviral load in infected patients. Preliminary results using clinical samples indicate a higher proviral load in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis than in asymptomatic carriers, and also suggest the usefulness of this quantitative measurement to assess the etiological link between HTLV-I and adult T-cell leukaemia/lymphoma-like syndromes.Journal of Virological Methods 05/2002; 102(1-2):37-51. · 2.01 Impact Factor
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- Journal of the Neurological Sciences (1)
- Transfusion (1)
- Journal of Virological Methods (1)
- Blood (1)
- PLoS Pathogens (1)
Institutions
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2004
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Hospital Centre University of Fort de France
Fort-de-France, MQ, Martinique
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