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1.  Dengue Seroprevalence in the French West Indies: A Prospective Study in Adult Blood Donors 
Using an anti-dengue immunoglobulin G (IgG) indirect enzyme-linked immunosorbent assay, seroprevalence was determined among 783 adult blood donors in the French Caribbean islands of Guadeloupe and Martinique in 2011. Overall, 93.5% [91.5; 95.1] samples were positive for dengue antibodies, 90.7% (350 of 386) in Martinique and 96.2% (382 of 397) in Guadeloupe. Only 30% of these adults recalled having had dengue disease before. Serotype-specific neutralization assays applied to a subset of IgG-positive samples indicated that a majority (77 of 96; 80%) reacted to the four serotypes. These seroprevalence findings are the first reported for Guadeloupe and Martinique and are consistent with the dengue epidemiology in these territories.
doi:10.4269/ajtmh.14-0211
PMCID: PMC4458816  PMID: 25846291
2.  HBZ Stimulates Brain-Derived Neurotrophic Factor/TrkB Autocrine/Paracrine Signaling To Promote Survival of Human T-Cell Leukemia Virus Type 1-Infected T Cells 
Journal of Virology  2014;88(22):13482-13494.
ABSTRACT
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that promotes neuronal proliferation, survival, and plasticity. These effects occur through autocrine and paracrine signaling events initiated by interactions between secreted BDNF and its high-affinity receptor, TrkB. A BDNF/TrkB autocrine/paracrine signaling loop has additionally been implicated in augmenting the survival of cells representing several human cancers and is associated with poor patient prognosis. Adult T-cell leukemia (ATL) is a fatal malignancy caused by infection with the complex retrovirus human T-cell leukemia virus type 1 (HTLV-1). In this study, we found that the HTLV-1-encoded protein HBZ activates expression of BDNF, and consistent with this effect, BDNF expression is elevated in HTLV-1-infected T-cell lines compared to uninfected T cells. Expression of TrkB is also higher in HTLV-1-infected T-cell lines than in uninfected T cells. Furthermore, levels of both BDNF and TrkB mRNAs are elevated in peripheral blood mononuclear cells (PBMCs) from ATL patients, and ATL patient sera contain higher concentrations of BDNF than sera from noninfected individuals. Finally, chemical inhibition of TrkB signaling increases apoptosis in HTLV-1-infected T cells and reduces phosphorylation of glycogen synthase kinase 3β (GSK-3β), a downstream target in the signaling pathway. These results suggest that HBZ contributes to an active BDNF/TrkB autocrine/paracrine signaling loop in HTLV-1-infected T cells that enhances the survival of these cells.
IMPORTANCE Infection with human T-cell leukemia virus type 1 (HTLV-1) can cause a rare form of leukemia designated adult T-cell leukemia (ATL). Because ATL patients are unresponsive to chemotherapy, this malignancy is fatal. As a retrovirus, HTLV-1 integrates its genome into a host cell chromosome in order to utilize host factors for replication and expression of viral proteins. However, in infected cells from ATL patients, the viral genome is frequently modified to block expression of all but a single viral protein. This protein, known as HBZ, is therefore believed to modulate cellular pathways necessary for the leukemic state and the chemotherapeutic resistance of the cell. Here we provide evidence to support this hypothesis. We found that HBZ promotes a BDNF/TrkB autocrine/paracrine signaling pathway that is known to enhance the survival and chemotherapeutic resistance of other types of cancer cells. It is possible that inhibition of this pathway may improve treatments for ATL.
doi:10.1128/JVI.02285-14
PMCID: PMC4249074  PMID: 25210182
3.  Evaluation of four commercial real-time RT-PCR kits for the detection of dengue viruses in clinical samples 
Virology Journal  2014;11:164.
Background
Dengue is the most frequent arthropod-borne viral disease worldwide. Because dengue manifestations are similar to those of many other febrile syndromes, the availability of dengue-specific laboratory tests is useful for the differential diagnosis. Timely and accurate diagnosis of dengue virus (DENV) infection is important for appropriate management of complications, pathophysiological studies, epidemiological investigations and optimization of vector-control measures. Several “in-house” reverse transcriptase-polymerase chain reaction (RT-PCR) methods have been developed to detect, type and/or quantify DENV. Standardized dengue RT-PCR kits with internal controls have been recently introduced, but need clinical evaluation. We assessed the performances of 4 commercial DENV real-time RT-PCR kits.
Findings
The 4 kits were evaluated using a panel of 162 samples positive with an existing in-place hemi-nested RT-PCR used for routine DENV-infection diagnosis in patients with acute-febrile disease. The panel included 46 DENV-1, 37 DENV-2, 33 DENV-3, and 46 DENV-4. Also, 70 negative serum specimens were used to determine specificity. Geno-Sen’s Dengue 1–4 Real-Time RT-PCR kit was the only assay to provide quantification using standards, but lacked sensitivity for DENV-4 detection. The SimplexaTM Dengue RT-PCR assay, with 151 (93.2% [95% confidence interval, 89.3–97.1]) positive samples, had significantly higher sensitivity than the other 3 kits; in a complementary evaluation of 111 consecutive patients’ samples, its performance and genotyping agreed with the hemi-nested gold-standard assay.
Conclusions
The SimplexaTM Dengue RT-PCR’s good performance to detect and genotype DENV1–4 requires further evaluation in multicenter and prospective studies, particularly in settings of clinical diagnosis during dengue outbreaks.
doi:10.1186/1743-422X-11-164
PMCID: PMC4177702  PMID: 25219286
Dengue; Diagnosis; Real-time polymerase chain reaction; RT (reverse transcription)-PCR; Genotype; Quantification; Commercial assays
7.  Human T-Cell Leukemia Virus Type 1 (HTLV-1) bZIP Factor Requires Cellular Transcription Factor JunD To Upregulate HTLV-1 Antisense Transcription from the 3′ Long Terminal Repeat 
Journal of Virology  2012;86(17):9070-9078.
Infection with the human T-cell leukemia virus type 1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia (ATL), a fatal malignancy characterized by the uncontrolled proliferation of virally infected CD4+ T cells. The HTLV-1 basic leucine zipper factor (HBZ) is believed to contribute to development and maintenance of ATL. Unlike the other HTLV-1 genes, the hbz gene is encoded on the complementary strand of the provirus and therefore is not under direct control of the promoter within the 5′ long terminal repeat (LTR) of the provirus. This promoter can undergo inactivating genetic or epigenetic changes during the course of ATL that eliminates expression of all viral genes except that of hbz. In contrast, repressive modifications are not known to occur on the hbz promoter located in the 3′ LTR, and hbz expression has been consistently detected in all ATL patient samples. Although Sp1 regulates basal transcription from the HBZ promoter, other factors that activate transcription remain undefined. In this study, we used a proviral reporter construct deleted of the 5′ LTR to show that HBZ upregulates its own expression through cooperation with JunD. Activation of antisense transcription was apparent in serum-deprived cells in which the level of JunD was elevated, and elimination of JunD expression by gene knockout or shRNA-mediated knockdown abrogated this effect. Activation through HBZ and JunD additionally required Sp1 binding at the hbz promoter. These data favor a model in which JunD is recruited to the promoter through Sp1, where it heterodimerizes with HBZ thereby enhancing its activity. Separately, hbz gene expression led to an increase in JunD abundance, and this effect correlated with emergence of features of transformed cells in immortalized fibroblasts. Overall, our results suggest that JunD represents a novel therapeutic target for the treatment of ATL.
doi:10.1128/JVI.00661-12
PMCID: PMC3416116  PMID: 22696638
8.  Relationship between Nonstructural Protein 1 Detection and Plasma Virus Load in Dengue Patients 
We report data from a prospective observational study performed in Martinique during a co-epidemic of dengue virus serotype 2 (DENV-2) and serotype 4 (DENV-4). Among 70 serum samples from patients with DENV-2 (n = 21) or DENV-4 (n = 49) infections, 47 (67.1%) were positive for dengue nonstructural protein 1 (NS1). Antigenemia correlated with plasma virus load and was independent of immune status and the time of sampling. Increased viremia 4–6 days after onset of illness was associated with NS1 positivity, secondary infection, and severe disease. Testing for NS1 could help identify the potentially most severely ill patients during the critical phase of dengue.
doi:10.4269/ajtmh.2010.10-0138
PMCID: PMC2929072  PMID: 20810841
11.  HTLV-1 Evades Type I Interferon Antiviral Signaling by Inducing the Suppressor of Cytokine Signaling 1 (SOCS1) 
PLoS Pathogens  2010;6(11):e1001177.
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.
Author Summary
Infection with HTLV-1 leads to the development of Adult T cell Leukemia (ATL) or 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. Using gene expression profiling of CD4+ T lymphocytes from HTLV-1 infected patients, we identified Suppressor of cytokine signaling 1 (SOCS1) as being highly expressed in HAM/TSP and AC patients. SOCS1 expression positively correlated with the high HTLV-1 mRNA load that is characteristic of HAM/TSP patients. SOCS1 inhibited cellular antiviral signaling during HTLV-1 infection by degrading IRF3, an essential transcription factor in the interferon pathway. Our study reveals a novel evasion mechanism utilized by HTLV-1 that leads to increased retroviral replication, without triggering the innate immune response.
doi:10.1371/journal.ppat.1001177
PMCID: PMC2973829  PMID: 21079688
12.  Dengue Type 3 Virus, Saint Martin, 2003–2004 
Emerging Infectious Diseases  2005;11(5):757-761.
We describe the spread of a dengue virus during an outbreak in Saint Martin island (French West Indies) during winter 2003–2004. Dengue type 3 viruses were isolated from 6 patients exhibiting clinical symptoms. This serotype had not been detected on the island during the preceding 3 years. Genome sequence determinations and analyses showed a common origin with dengue type 3 viruses isolated in Martinique 2 years earlier.
doi:10.3201/eid1105.040959
PMCID: PMC3320377  PMID: 15890134
Dengue Virus; French west indies; molecular epidemiology
13.  Increased proviral load in HTLV-1-infected patients with rheumatoid arthritis or connective tissue disease 
Retrovirology  2005;2:4.
Background
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.
Results
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.
Conclusions
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.
doi:10.1186/1742-4690-2-4
PMCID: PMC549050  PMID: 15686595
14.  Hepatitis C Virus (HCV) Genotypes in the Caribbean Island of Martinique: Evidence for a Large Radiation of HCV-2 and for a Recent Introduction from Europe of HCV-4 
Journal of Clinical Microbiology  2004;42(2):784-791.
Molecular epidemiological studies of hepatitis C virus (HCV) in the Caribbean may help to specify the origin and spread of HCV infection. Indeed, the Caribbean population is intermixed from European and African origins and geographically close to the American continent. We characterized HCV genotypes in the Caribbean island of Martinique. HCV genotypes were analyzed by sequencing or reverse hybridization in the 5′ noncoding region (5′NC) in 250 HCV-monoinfected and 85 HCV-human immunodeficiency virus (HIV)-coinfected patients. In addition, sequencing in the nonstructural 5B (NS5B) gene was required to determine the subtype or to perform phylogenetic analysis in selected samples. Genotypes 1 to 6 were found, respectively, in 84.4, 6.8, 5.2, 2.8, 0.4, and 0.4% of 250 HCV-monoinfected patients and in 71.7, 7.1, 15.3, 5.9, 0, and 0% of 85 HCV-HIV-coinfected patients. HCV-1b was found in 66.4% of the HCV-monoinfected patients and was associated with blood transfusion, whereas HCV-1a was detected in 41.2% of the HCV-HIV-coinfected patients and was associated with intravenous drug use (IVDU). The HCV-3 strains belonged to subtype 3a and were linked to IVDU. Phylogenetic analyses were focused on HCV-2 and HCV-4, which are common in Africa. Two opposite patterns were evidenced. NS5B sequences from 19 HCV-2 isolates were affiliated with many different subtypes described either in Europe or in West Africa, suggesting an ancient radiation. In contrast, seven of the nine HCV-4 NS5B sequences ranged within HCV-4a and HCV-4d clusters spreading in continental France by the IVDU route. Epidemiological data demonstrate the recent introduction of HCV-4a and -4d subtypes into the Caribbean.
doi:10.1128/JCM.42.2.784-791.2004
PMCID: PMC344442  PMID: 14766854

Results 1-14 (14)