Human T-cell Lymphotropic Virus Type 1 Infection Research Articles

Treatment of strongyloidiasis in HTLV-1 and Strongyloides stercoralis coinfected patients is associated with increased TNFα and decreased soluble IL2 receptor levels

Human T cell lymphotropic virus type 1 (HTLV-1) infection has been associated with recurrent and disseminated strongyloidiasis and adult T cell leukemia/lymphoma (ATLL). We compared immunological aspects and markers for ATLL in HTLV-1 patients with or without strongyloidiasis, and evaluated the influence of Strongyloides stercoralis treatment on the immune response and clinical outcomes of HTLV-1 infection. Levels of TNFα and IFNγ were lower in patients coinfected with HTLV-1 and S. stercoralis than in patients with HTLV-1 only (p < 0.05), and there was an increase in TNFα levels after anthelmintic treatment. Levels of sIL-2R were higher in patients with HTLV-1 coinfected with S. stercoralis and anthelmintic treatment decreased sIL-2R levels (p < 0.05). The one patient who developed ATLL was coinfected with S. stercoralis. These data show that helminthic infection has a modulatory role in HTLV-1 infection and that S. stercoralis may be a cofactor in the development of ATLL.

Schistosoma Antigens Downmodulate the in vitro Inflammatory Response in Individuals Infected with Human T Cell Lymphotropic Virus Type 1

Human T cell lymphotropic virus type 1 (HTLV-1) is the causal agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). While the immune response to HTLV-1 infection is polarized to the Th1-type, chronic helminth infections drive the Th2- and T regulatory-type, and are able to downregulate the inflammatory response in some autoimmune diseases. Objective: To evaluate whether Schistosoma spp. antigens alter the in vitro cytokine response in HTLV-1 infection. Methods: The recombinant Schistosoma antigens Sm29 and ShTSP2 (tetraspanin) and PIII, a fraction of the Schistosoma mansoni adult worm antigen were added to peripheral blood mononuclear cell (PBMC) cultures of HTLV-1-infected individuals and the levels of interferon (IFN)-γ and interleukin (IL)-10 in the supernatants were measured using the ELISA sandwich technique. Results: Compared to the levels of cytokine in nonstimulated cultures, the levels of IFN-γ were reduced in 50, 47 and 50% of patients by the presence of Sm29, ShTsp2 and PIII, respectively. The downregulation of IFN-γ production in the presence of Sm29 antigen was observed mainly in subjects who had lower basal levels of this cytokine. The levels of IL-10, however, increased by the addition of the three antigens in the cultures in 74, 62 and 44% of individuals, respectively. In addition, there was a decrease in the ratio of IFN-γ/IL-10 levels in cultures stimulated with Sm29 and ShTSP2 when compared to nonstimulated ones. Conclusions: The Schistosoma spp. antigens used in this study were able to downmodulate IFN-γ production in vitro in HTLV-1 infection. This may be associated with the increased levels of IL-10 induced by the antigens.

Phylogenetic Analysis of Human T Cell Lymphotropic Virus Type 1 Isolated from Cuban Individuals

The presence of infection by human T cell lymphotropic virus type 1 (HTLV-1) in Cuba has been previously documented. However, genetic information on the strains that circulate in the Cuban people remains unknown. The present work constitutes the first study of phylogenetic relationship of HTLV-1 Cuban isolates. Twelve Cuban patients who were diagnosed with HTLV-1 infection and had different clinical manifestations were studied. The 3' LTR sequences were analyzed for the construction of a phylogenetic tree with reference sequences of HTLV-1 of different geographic origins. Phylogenetic analysis of the 3' LTR gene showed that all the Cuban samples clustered in the Transcontinental subgroup of the Cosmopolitan subtype. Phylogenetic analysis suggests multiple introductions of HTLV-1 in Cuba as well as a possible African origin of the samples. The results of the study will reinforce the program of epidemic surveillance of the infection in Cuba.

Modulation of glutathione intracellular levels alters the spontaneous proliferation of lymphocyte from HTLV-1 infected patients

The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus associated with neoplasias and inflammatory diseases, such as adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1-infected individuals present a spontaneous T lymphocyte proliferation. This phenomenon is related to the HTLV-1-proviral load and the persistence of the infection. Viral proteins induce many cellular mediators, which can be associated with the abnormal cellular proliferation. The intracellular levels of glutathione (GSH) are important to modulate the cellular proliferation. The aim of this study was to investigate the correlation between the modulation of intracellular GSH levels and the spontaneous lymphocyte proliferation during the HTLV-1 infection. Intracellular GSH level can be modulated by using dl-buthionine-[S,R]-sulfoximine (BSO, GSH synthesis inhibitor) and N-acetylcysteine (NAC, peptide precursor). Our results demonstrated that BSO was capable of inducing a decrease in the spontaneous proliferation of PBMC derived from HTLV-1 carriers. On the other hand, the GSH precursor induces an increase in mitogen-stimulated cellular proliferation in infected and uninfected individuals. Similar results were observed by the inhibition of ABCC1/MRP1 protein, augmenting the mitogen-induced proliferation. This effect can be related with an increase in the GSH levels since ABCC1/MRP1 transports GSH to the extracellular medium. There was a significant difference on the expression of CD69 and CD25 molecules during the lymphocyte activation. We did not observe any alterations on CD25 expression induced by BSO or NAC. However, our results demonstrated that NAC treatment induced an increase in CD69 expression on unstimulated CD8+ T lymphocytes obtained from HTLV-1 infected individuals, healthy donors and HTLV carriers. Therefore, our results suggest that the cellular proliferation promoted by the infection with HTLV-1 and the activation phenotype of CD8+ T lymphocytes can be regulated by changing the intracellular GSH levels; suggesting the modulation of these intracellular levels as a new approach for the treatment of pathologies associated with the HTLV-1 infection.

P101 The MHC-II transactivator CIITA inhibits Tax-1-mediated HTLV-1 expression and NF-kBactivation

Human T-cell Lymphotropic Virus type-1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Many evidences have shown that constitutive activation of NF-kB pathway by Tax-1 is crucial for T-cell transformation. We demonstrate that CIITA, the master regulator of MHC class II gene transcription, inhibits HTLV-1 replication by blocking the function of the viral transactivator Tax-1 both when exogenously transfected in 293T cells and when endogenously expressed by a subset of U937 promonocytic cells. Tax-1 and CIITA physically interact in vivo. CIITA residues from positions 64-124 are required to block Tax-1 transactivation and this inhibitory action correlates with the nuclear localization of CIITA. CIITA severely impairs the physical and functional interaction of Tax-1 with the cellular co-activators PCAF, CREB and ATF1, which are required for the optimal activation of HTLV-1 promoter. Accordingly, the over-expression of PCAF, CREB and ATF1restore Tax-1-dependent transactivation of the viral LTR promoter inhibited by CIITA. Interestingly, CIITA inhibits also Tax-1-mediated activation of the NF-kB pathway, suggesting that its newly discovered function as viral restriction factor in HTLV-1 infection may also result in a suppression of Tax-1-induced cellular transformation. Thus, assessing the molecular basis of CIITA-mediated Tax-1 inhibition may be important in defining new strategies to control HTLV-1 spreading and oncogenic potential.

In Memoriam – Hugh A. Smythe, 1927–2012

<h3>Objective</h3> To test the hypothesis that teriflunomide can reduce ex vivo spontaneous proliferation of peripheral blood mononuclear cells (PBMCs) from patients with human T-cell lymphotropic virus type 1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP). <h3>Methods</h3> PBMCs from patients with HAM/TSP were cultured in the presence and absence of teriflunomide and assessed for cell viability, lymphocyte proliferation, activation markers, HTLV-1 <i>tax</i> and HTLV-1 <i>hbz</i> messenger ribonucleic acid (mRNA) expression, and HTLV-1 Tax protein expression. <h3>Results</h3> In culture, teriflunomide did not affect cell viability. A concentration-dependent reduction in spontaneous proliferation of PBMCs was observed with 25 μM (38.3% inhibition), 50 μM (65.8% inhibition), and 100 μM (90.7% inhibition) teriflunomide. The inhibitory effects of teriflunomide were detected in both CD8⁺ and CD4⁺ T-cell subsets, which are involved in the immune response to HTLV-1 infection and the pathogenesis of HAM/TSP. There was no significant change in HTLV-1 proviral load (PVL) or <i>tax</i> mRNA/Tax protein expression in these short-term cultures, but there was a significant reduction of HTLV-1 PVL due to inhibition of proliferation of CD4⁺ T cells obtained from a subset of patients with HAM/TSP. <h3>Conclusions</h3> These results suggest that teriflunomide inhibits abnormal T-cell proliferation associated with HTLV-1 infection and may have potential as a therapeutic option in patients with HAM/TSP.

Dengue fever and human T-cell lymphotropic virus type 1 infection

Globalization has increased both the number of emergent diseases and the diversity of co-infections, which could in turn mutually influence the pathogenesis of well-known infectious diseases. Here, we report the first series of chronic human T-cell lymphotropic virus type 1 (HTLV-1) patients co-infected with the dengue fever virus. As both of these diseases are immuno-mediated, we anticipated interference in the development of both diseases, with atypical clinical and laboratory parameter results. All the patients had classic dengue fever, and the main outstanding abnormality was leukopenia associated with lymphopenia. Although a mutual influence was expected, dengue fever did not affect the clinical course of HTLV-1 infection, and HTLV-1 proviral loads revealed unpredictable patterns of change.

Effects of exogenous interleukin-7 on CD8(+) T-cell survival and function in human T-cell lymphotropic virus type 1 infection

Interleukin-7 (IL-7) mediates T-cell homeostasis through its effects on T-cell development, survival and function. In human T-cell lymphotropic virus type 1 (HTLV-1) infection, which is causally implicated in adult T-cell leukemia (ATL), the efficiency with which CD8(+) cytotoxic T-lymphocytes (CTLs) clear HTLV-1-infected cells mediates viral control and may be related to disease progression. We report here that CD127 expression in CD8(+) T-cells is independently related to disease status, and that exogenous IL-7 enhances CD8(+) T-cell survival and clearance of HTLV-1 infected cells in vitro. We conclude that CD127 down-regulation may be associated with disease status in HTLV-1 infection, and propose that exogenous IL-7 may be useful immunotherapy or cytokine adjuvant for an anti-ATL therapeutic vaccine.

ROLE OF CD48 IN REGULATION OF T-CELL MEDIATED IMMUNITY IN HTLV-1 INFECTION

Event Abstract Back to Event ROLE OF CD48 IN REGULATION OF T-CELL MEDIATED IMMUNITY IN HTLV-1 INFECTION Chioma E. Chibueze-Nnorom1, Yohann White2, Makoto Yoshimitsu1* and Naomichi Arima1* 1 Center for Chronic Viral Diseases Graduate School of Medical and Dental Sciences Kagoshima University, Hematology and Immunology, Japan 2 University of West Indies, Mona Kingston, Jamaica HTLV-1 (Human T cell lymphotropic virus type 1) infection is associated with an aggressive T cell malignancy ATLL (Adult T-cell leukemia/lymphoma), the virus also establishes lifelong persistent infection in humans resulting in a carrier state (clinically asymptomatic). CD48 is a GPI anchored cell surface molecule ubiquitously expressed on various hematopoietic cells, its expression has been shown to be up-regulated in viral infections as a sign of ongoing breach of immunity and therefore facilitates immune response. In HTLV-1 infection, one of the factors suggested to play a role in its persistence is the increased expression of the trans-activating viral gene encoding HTLV-1 tax among others; tax protein is the dominant target antigen of the T cell response to HTLV-1 in infected individuals. In this study, we investigate the role of CD48 in HTLV-infection, we show that it is down regulated in HTLV-1 infection; the presence of HTLV-1 tax protein also suppresses CD48 expression. On blockade using anti-CD48 AB (antibody), the effector function of T cells in terms of cytokine production improved. Thus, we propose a possible means of immune evasion by HTLV-1 virus by Cd48 down-regulation and a possible inhibitory role in HTLV-1 infection.

Reproductive Decisions among People Living with Human T-cell Lymphotropic Virus Type 1 (HTLV-1)

Background: Human T-cell Lymphotropic Virus type 1 (HTLV-1) infection is a neglected public health problem. The majority of carriers is asymptomatic and may have a low risk of developing related diseases. The aims of this study were to discuss reproductive decisions of women and men living with HTLV-1 infection to assess their perception of infection and associated diseases, expectations regarding Mother-to-Child Transmission (MTCT), and whether health care conditions may affect their reproductive decisions. Methods: A qualitative study with 13 adult HTLV-1-seropositive subjects without co-infections. For data analysis, life history trajectories and categories of discourse were constructed for each respondent. Results: Reproductive decisions required the reassessment of life projects in the new context of HTLV-1 infection. Thus, a child remains representative of a “new meaning to life”. There is a need for accurate information regarding the risk of MTCT and the transmission risk to a serodiscordant partner while trying to conceive. It was also observed that a couple’s relationship and emotional dynamics were crucial in the process of making reproductive decisions. It was emphasized that the inhibition of breastfeeding was seen as a reliable method in preventing transmission, favouring the decision to have a child. Conclusions: Reproductive decisions were influenced by information transmitted by healthcare providers that only rarely does a person with HTLV-1 become sick due to the infection. Because this infection is incurable, reproductive decisions are crucial. The importance of reproductive decisions highlight the need for accurate information dissemination and infection prevention, perhaps only made possible through effective interdisciplinary means.

Short Communication: Aggressive Adult T Cell Leukemia/Lymphoma: The Tip of the Iceberg of the Hidden Human T Cell Lymphotropic Virus Type 1 Infection Burden in Nonendemic Countries

Adult T cell leukemia/lymphoma has only rarely been reported in Europe. We aimed to determine the clinical characteristics and outcome of adult T cell leukemia/lymphoma patients in a nonendemic country. Cases of adult T cell leukemia/lymphoma managed at Hospital Universitari Vall d'Hebron, Barcelona, Spain were reviewed. Information on the foreign population living in Spain, according to country of origin, was obtained using official published data from the National Statistics Institute. Three patients were diagnosed with adult T cell leukemia/lymphoma between 2003 and 2010. Two cases were of the acute subtype and one case of the lymphoma subtype. Two patients were female and the mean age at presentation was 41.3 years. Patients originated from three different countries. The characteristics of the attended patients include widespread enlargement of the lymph nodes, a variety of multiple extranodal involvements, bone marrow infiltration, and a high incidence of infections including latent parasitic infections. Prototypic adult T cell leukemia/lymphoma presenting with high white cell counts, flower cells, and hypercalcemia was not observed. Regarding therapy, one patient received chemotherapy alone and two subjects combined first-line therapy including antiviral drugs. Of the three patients, two are dead (mean survival time 6 months) and one has been lost to follow-up. We estimate that at least 15,000 people living in Spain are infected with human T cell lymphotropic virus type 1 (HTLV-1). Adult T cell leukemia/lymphoma is a heterogeneous disease that often presents without distinguishing or prototypical features. A high index of clinical suspicion is essential for diagnosis. Several epidemiological differences have been observed in different countries. Today, HTLV-1 infection is highly underdiagnosed.

Co‐presentation of human T‐cell lymphotropic virus type 1 (HTLV‐1)‐associated myelopathy/tropical spastic paraparesis and adult‐onset infective dermatitis associated with HTLV‐1 infection

Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), infective dermatitis associated with HTLV-1 (IDH), and various other clinical conditions. Several of these diseases can occur in association. Report an association of diseases related to HTLV-1 infection, occurring in an unusual age group. Dermatological and laboratory exams were consecutively performed in HTLV-1-infected individuals from January 2008 to July 2010 in the HTLV Outpatient Clinic at the Institute of Infectious Diseases "Emilio Ribas" in São Paulo, Brazil. A total of 193 individuals (73 HAM/TSP and 120 asymptomatic carriers) were evaluated, three of which were associated with adult-onset IDH and HAM/TSP. In all three cases, the patients were affected by IDH after the development and progression of HAM/TSP-associated symptoms. Small number of cases because of the rarity of these diseases. We draw attention to the possibility of co-presentation of adult-onset IDH in patients with a previous diagnosis of HAM/TSP, although IDH is a disease classically described in children. Thus, dermatologists should be aware of these diagnoses in areas endemic for HTLV-1 infection.

Immune Exhaustion and 2B4 Expression in Human T-Cell Lymphotropic Virus Type 1(HTLV-1) Infection

AbstractAbstract 4807 Background:The role of the 2B4/CD48 pathway in chronic viral infections has been controversial, with some studies suggesting an enhancing and others an inhibitory effect on virus specific CD8 (+) cytotoxic T-lymphocytes. Human T-cell lymphotropic virus type 1 (HTLV-1) trans-activating (Tax) protein is crucial for viral replication and activates HTLV-1 gene transcription. Methods:Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll centrifugation and cryopreserved until use. For staining, cells were incubated with fluorochrome-conjugated antibodies against 2B4, CD48, CD4, CD8. CD8 (+) lymphocytes were identified using phycoerythrin (PE) labeled tetramers HLA*0201 or 2402 Tax, CMV and EBV immune-dominant epitopes. In some, cells were fixed and permeabilized prior to staining with FITC-conjugated anti-Tax protein (clone Lt-4) antibodies or a control IgG. To examine the effect of CD48 blockade on Cd8+ T lymphocyte function, PBMCs (1 × 106) were cultured in complete medium (RPMI-1640 supplemented with 100U/ml penicillin, 0.1mg/ml streptomycin, 0.05mM 2-mercaptoethanol, 50U/ml recombinant interleukin-2 and 10% inactivated FCS) with/without Tax peptide and/or anti-CD48 blocking antibody (5μg/ml) in the presence of brefeldin or monensin for intracellular perforin or surface degranulation of CD107a, respectively. Acquisition was done using FACS Calibur or FACS Scan flow-cytometer and analyzed with Flowjo software. Differences were analyzed by Mann-Whitney U test; changes pre- and post- ex-vivo culture were analyzed by Wilcoxon matched pairs test using Stata software version 9 (StataCorp LP). P-values <0.05 were considered significant. Results:The expression of 2B4 in total CD8 (+) T-cells was significantly greater in HTLV-1 infected individuals compared to healthy controls(67.2±17.6 and 51.6±21.4, respectively; p 0.03; n = 11 HCs, 44 infected; Figure 1b), there was no difference in 2B4 expression in HTLV-1 tetramer specific CD8 (+) CTLs between asymptomatic HTLV-1 infected (ACs) and ATLL (81.0±18.5 and 73.2±24.8, respectively; n = 23 ACs, 19 ATLLs; Figure 1d) individuals.In CMV specific CTLs, 2B4 expression was significantly higher in HTLV-1 infected individuals compared with uninfected healthy controls (77.4±21.8 and 46.7±29.5, respectively; p = 0.01, n = 28 infected and 7 HCs; Figure 1D); and 2B4 expression was also greater in EBV-specific CTLs in HTLV-1 infected individuals compared with uninfected healthy controls (72.7±22.1 and 46.5±26.3, respectively; p = 0.02; n = 27 infected and 6 HCs; Figure 1d).HTLV-1 infected cells express intracellular HTLV-1 Tax protein in ex vivo cultures, peaking at 16 to 18 hours followed by a marked fall to undetectable levels. In our study, we noticed a trend whereby CD48 expression was lower in intracellular Tax-protein expressing (infected) CD4 (+) cells compared to Tax protein-negative (uninfected cells) in short term ex vivo cultures (50.6±7.3% versus 90.1±5.6%, respectively); and CD48 expression in total CD4 (+) cells was downregulated as Tax protein became expressed in cultures (93.3±3.3 at start versus 86.7±6.1 after culture; 3 independent experiments; Figure 2). Programmed death ligand 1 (PDL1) is known to be upregulated in Tax-protein expressing compared with Tax-negative cells, which is believed to permit immune evasion by HTLV-1 infected cells, but the proportion of HTLV-1 infected cells that are CD48(+) appears to be down regulated in this study. In vitro infection of target cells with EBV has been shown to upregulate CD48 expression at the mRNA and protein levels; thus, indicating that downregulation of CD48 in HTLV-1 infected cells is unique, possibly related to interactions of the trans-activating viral protein with host gene regulatory mechanisms at molecular level.Further, perforin production by CD8(+) lymphocytes is known to mediate lysis of HTLV-1 infected cells, in our study, the CD48 antibody resulted in increased perforin production by CD8 (+) CTLs, suggesting an inhibitory role for the 2B4/CD48 pathway in HTLV-1 infection(Figure 3c).Similarly, expression of the degranulation marker, CD107a in CD8 (+) lymphocytes was augmented with CD48 blocking antibody (Figure 3a, b). Conclusion:The pattern of 2B4 expression in HTLV-1 infection and enhanced CD8 (+) lymphocyte function with 2B4/CD48 blockade suggest involvement of this pathway in immune exhaustion, and a possible immunotherapeutic target. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

HTLV‐1‐associated infective dermatitis: updates on the pathogenesis

HTLV-1-associated infective dermatitis (HAID) is the main paediatric manifestation of human T-cell lymphotropic virus type 1 (HTLV-1). It is characterised by a chronic exudative eczematous eruption and persistent infection with Staphylococcus aureus (SA) and beta-haemolytic streptococci (BHS). Prevalence is highest in the Caribbean and Brazil; however, cases have been reported in other HTLV-1 endemic regions. Approximately 20 million people worldwide are infected with HTLV-1 and only 5-10% suffer from disease. Other manifestations include adult T-cell leukaemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). HAID may also progress to ATLL or TSP/HAM. Treatment options are limited to prolonged antibiotic therapy. The aim of this paper is to review existing evidence and propose new theories on the pathogenesis of HAID. The current view is that HTLV-1 infection is required and in susceptible individuals leads to immune dysregulation with subsequent immunosuppression and superinfection with SA and BHS. Evidence suggests that host, environment and genetic factors may play a causative role. Genetic factors within ethnic groups determine host immune response and carrier state or disease manifestation of HTLV-1 infection. Increased IgE levels may contribute to the SA and BHS superinfection in HAID. Additionally, the possible impact of filaggrin, skin proteinase dysregulation, Langerhans cell dysfunction and TH2 chemokines is highlighted. More than 45years since the discovery of HAID, the exact pathogenesis is still not fully understood. Further research is still needed to clearly elucidate the exact pathogenic mechanism of HAID.

Human T Cell Lymphotropic Virus Type 1 Viral Load Variability and Long-Term Trends in Asymptomatic Carriers and in Patients with Human T Cell Lymphotropic Virus Type 1-Related Diseases

Human T cell lymphotropic virus type 1 (HTLV-1) proviral load (PVL) in peripheral blood mononuclear cells (PBMCs) is high in patients with adult T cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and in some asymptomatic carriers, but fluctuates. Our objectives were to document ranges of HTLV PVL across a broader spectrum of diseases and tissues, to quantify the normal range of intrapatient PVL variability, and to identify which PVL values and changes deserve further investigation. PVL was measured in 191 patients with HTLV-1-associated diseases and in 211 asymptomatic carriers, using real-time quantitative PCR. The intraassay variability increases as viral load decreases: 8% at high load, 17% at medium load, and 33% at low load. The interassay variability is not different from the intraassay. Mean intrapatient CV is 65% (SD 21) in asymptomatic carriers and 59% (SD 22) in HAM/TSP. PVL values varied widely between individuals, but were relatively constant within individuals. High PVL in cerebrospinal fluid (CSF) and lymph nodes (LN) was associated with disease but 57% of asymptomatic carriers had a PVL greater than 1% in PBMCs. Our results suggest that (1) PVL changes falling outside a coefficient of variation of 100% require more detailed assessment, (2) asymptomatic carriers with PVL higher than 10% should undergo more frequent clinical and laboratory monitoring, and (3) HTLV-1 PVL in blood and tissue is helpful in the diagnosis and monitoring of HTLV-1 infection.

A Public HTLV-1 Molecular Epidemiology Database for Sequence Management and Data Mining

BackgroundIt is estimated that 15 to 20 million people are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). At present, there are more than 2,000 unique HTLV-1 isolate sequences published. A central database to aggregate sequence information from a range of epidemiological aspects including HTLV-1 infections, pathogenesis, origins, and evolutionary dynamics would be useful to scientists and physicians worldwide. Described here, we have developed a database that collects and annotates sequence data and can be accessed through a user-friendly search interface. The HTLV-1 Molecular Epidemiology Database website is available at http://htlv1db.bahia.fiocruz.br/.Methodology/Principal FindingsAll data was obtained from publications available at GenBank or through contact with the authors. The database was developed using Apache Webserver 2.1.6 and SGBD MySQL. The webpage interfaces were developed in HTML and sever-side scripting written in PHP. The HTLV-1 Molecular Epidemiology Database is hosted on the Gonçalo Moniz/FIOCRUZ Research Center server. There are currently 2,457 registered sequences with 2,024 (82.37%) of those sequences representing unique isolates. Of these sequences, 803 (39.67%) contain information about clinical status (TSP/HAM, 17.19%; ATL, 7.41%; asymptomatic, 12.89%; other diseases, 2.17%; and no information, 60.32%). Further, 7.26% of sequences contain information on patient gender while 5.23% of sequences provide the age of the patient.Conclusions/SignificanceThe HTLV-1 Molecular Epidemiology Database retrieves and stores annotated HTLV-1 proviral sequences from clinical, epidemiological, and geographical studies. The collected sequences and related information are now accessible on a publically available and user-friendly website. This open-access database will support clinical research and vaccine development related to viral genotype.

A 29-Year-Old Renal Transplant Recipient with Acute Respiratory Failure

A 29-year-old woman was admitted with a 2-day history of fever, cough, hemoptysis, abdominal pain, and diarrhea. She had received a renal transplantation 4 months before and was receiving mycophenolate mofetil, tacrolimus, and prednisone. Two days after admission, she developed a petechial rash on the abdomen (Figure 1), paralytic ileus, and progressive respiratory distress requiring mechanical ventilation. The white blood cell count was 4,300, with 12% eosinophils, blood cultures were negative, serological tests for human immunodeficiency virus (HIV), human T-cell lymphotropic virus type 1 (HTLV-1), and cryptococcal antigen were negative, and plasma viral load for cytomegalovirus (CMV) was negative. The chest X-ray showed bilateral interstitial infiltrates (Figure 2). A bronchoalveolar lavage tested negative for bacteria, galactomannan antigen, mycobacteria, and fungi, but it disclosed rabditiform larvae of Strongyloides stercolaris (Figure 3), which were also found in the stools. She was started on ivermectin and broad antibiotic coverage but died of multiorgan failure 4 days later. Strongyloidiasis is a well-known complication of severe immunosupression. Conditions such as HIV and HTLV-1 infections, chronic use of steroids, chemotherapy, diabetes, hematologic malignancies, and malnutrition pre-dispose to the hyperinfection syndrome, which carries high mortality rates.1 Pre-transplant patients and donors in endemic areas should always be investigated for Strongyloides infection, for which treatment with ivermectin is indicated.2 Figure 1. Petechial rash located on the abdomen. Figure 2. Chest X-ray showing bilateral interstitial and alveolar infiltrates. Figure 3. Rabditiform larva of S. stercoralis found in the bronchoalveolar lavage.

Maternal Proviral Load and Vertical Transmission of Human T Cell Lymphotropic Virus Type 1 in Guinea-Bissau

The relative importance of routes of transmission of human T cell lymphotropic virus type 1 (HTLV-1) in Guinea-Bissau is largely unknown; vertical transmission is thought to be important, but there are very few existing data. We aimed to examine factors associated with transmission in mothers and children in Guinea-Bissau, where HTLV-1 is endemic (prevalence of 5% in the adult population). A cross-sectional survey was performed among mothers and their children (aged <15 years) in a rural community in Guinea-Bissau. A questionnaire to identify risk factors for infection and a blood sample were obtained. HTLV-1 proviral load in peripheral blood was determined and PCR was performed to compare long terminal repeat (LTR) sequences in mother-child pairs. Fourteen out of 55 children (25%) of 31 HTLV-1-infected mothers were infected versus none of 70 children of 30 uninfected mothers. The only factor significantly associated with HTLV-1 infection in the child was the proviral load of the mother; the risk of infection increased significantly with the log(10) proviral load in the mother's peripheral blood (OR 5.5, 95% CI 2.1-14.6, per quartile), adjusted for weaning age and maternal income. HTLV-1 sequences of the LTR region obtained from mother-child pairs were identical within pairs but differed between the pairs. Vertical transmission plays an important role in HTLV-1 transmission in this community in Guinea-Bissau. The risk of transmission increases with the mother's proviral load in the peripheral blood. Identical sequences in mother-child pairs give additional support to the maternal source of the children's infection.

Helminthic infection and the risk of neurologic disease progression in HTLV-1

BackgroundInfection with the human T-cell lymphotropic virus, type 1 (HTLV-1) has been associated with an increased Th1 response. Interestingly, a higher prevalence of helminthic coinfection has been observed among infected individuals, and subsequent modulation of the immune response typically associated with helminths may influence clinical outcomes among HTLV-1 coinfected individuals. ObjectiveThis study was conducted to elucidate the association between helminthic coinfection and the development of clinically characterized neurologic disease that occurs in HTLV-1 infection. Study designIn a cohort analysis, incidence of HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was recorded. Incidence of clinical outcomes and disease-free survival of several neurologic outcomes associated with HTLV-1 were estimated using the Kaplan–Meier method with log-rank tests. The relationships between helminthic infection and risk of HTLV-1 neurologic outcomes were assessed by Cox proportional hazard modeling. ResultsSeventy-four coinfected and 79 non-coinfected patients were followed, with 92 helminthic infections observed in the coinfected group. One patient per group developed HAM/TSP and the risk of progression to neurologic disease outcomes did not differ among those with and without helminthic coinfection (p>0.45). A significant difference was noted in the prevalence of neurologic disease outcomes among all patients at the conclusion of the study (p<0.01). ConclusionsThese data suggest that treated helminthic infection does not affect risk of development of neurologic disease in HTLV-1 infection, and reinforce that treatment of helminths does not adversely affect patients with HTLV-1. Importantly, among all patients, an overall progression of neurologic disease was observed.

DC-SIGN a potential new target for antiretroviral (HTLV/HIV) drug discovery

August 20-22, 2012 D the susceptibility of dendritic cells (DCs) to human T-cell lymphotropic virus type 1 (HTLV-1) infection and the defined role of these cells in disease pathogenesis, the mechanisms of viral binding to DCs have not been fully delineated. Recently, a glucose transporter GLUT-1, heparan sulfate proteoglycans (HSPGs), and neuropilin-1 (NRP-1) were demonstrated to facilitate HTLV-1 entry into T cells. DCs express their own array of antigen receptors, the most important being the DC-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) with respect to retrovirus binding. Consequently, the role of DC-SIGN and other HTLV-1 attachment factors was analyzed in viral binding, transmission, and productive infection using monocyte-derived DCs (MDDCs), blood myeloid DCs, and B-cell lines expressing DC-SIGN. The relative expression of DC-SIGN, GLUT-1, HSPGs, and NRP-1 was first examined on both DCs and B-cell lines. Although inhibition of these molecules reduced viral binding, HTLV-1 transmission from DCs to T cells was mediated primarily by DC-SIGN. DC-SIGN was also shown to play a role in the infection of MDDCs as well as model B-cell lines. HTLV-1 infection of MDDCs was also achieved in blood myeloid DCs following the enhancement of virus-induced interleukin-4 production and subsequent DC-SIGN expression in this cell population. This study represents the first comprehensive analysis of potential HTLV-1 receptors on DCs and strongly suggests that DC-SIGN plays a critical role in HTLV-1 binding, transmission, and infection, thereby providing an attractive target for the development of antiretroviral therapeutics and microbicides. In this respect, we have developed both cell-based and cell-free high throughput screening assays in order to identify novel inhibitors of DC-SIGN interaction with HTLV-1 gp46 and HIV-1 gp120 proteins.