ABSTRACT
The present study compares the ability of distinct immunological assays (chemiluminescence immunoassay-CLIA, western blot-WB and flow cytometry-FC-Simplex and Duplex) to detect anti-HTLV (human T-lymphotropic virus) antibodies in candidates for blood donations at the Amazonas State Blood Center (Brazil) between January 2018 and December 2022. Overall, 257,942 samples from candidates for blood donations were screened using CLIA, which led to 0.15% seropositivity for HTLV (409 samples). A total of 151 candidates for blood donations were enrolled for retesting with CLIA followed by additional testing using WB and FC-Simplex and Duplex analysis. Our results demonstrated that 62% (93/151), 20% (30/151) and 17% (26/151) of the samples presented positive results with retesting using CLIA, WB and FC-Simplex analysis, respectively. Additional analysis of the CLIA, WB and FC-Simplex results revealed an overall agreement of 56% for CLIA and WB (22 co-negative; 30 co-positive samples), 48% for CLIA and FC-Simplex (21 co-negative; 24 co-positive samples) and 80% for WB and FC-Simplex (51 co-negative; 23 co-positive samples). Considering the WB as the reference standard for the diagnosis of infection with HTLV-1/2, we observed that the CLIA results of ≤3.0 RLU and >10.0 RLU in the retest can be used define a negative or positive result, respectively, and could be used as new specific cut-off values. The overall agreement between WB and FC-Duplex for accomplishing the differential diagnosis was evaluated and demonstrated 100% correspondence for the diagnosis of HTLV-1 (15/15) and HTLV-2 (7/7). Our findings demonstrate that gaps in the diagnosis of infection with HTLV-1/2 could be overcome by the simultaneous use of distinct immunological assays during retesting of candidates for blood donations.
Subject(s)
Blood Donors , HTLV-I Infections , HTLV-II Infections , Human T-lymphotropic virus 1 , Human T-lymphotropic virus 2 , Humans , Brazil , HTLV-I Infections/diagnosis , HTLV-I Infections/blood , HTLV-I Infections/immunology , HTLV-II Infections/diagnosis , HTLV-II Infections/blood , Human T-lymphotropic virus 1/immunology , Human T-lymphotropic virus 1/isolation & purification , Human T-lymphotropic virus 2/immunology , Male , Female , Adult , Diagnosis, Differential , Middle Aged , Blotting, Western , Flow Cytometry/methods , Blood DonationABSTRACT
Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997-2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Rα, IL-27) or HAM (IL-29/IFN-λ1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients.
Subject(s)
Biomarkers , Human T-lymphotropic virus 1 , Interleukin-10 , Viral Load , Humans , Female , Male , Brazil/epidemiology , Human T-lymphotropic virus 1/immunology , Interleukin-10/blood , Biomarkers/blood , Middle Aged , Adult , HTLV-I Infections/immunology , HTLV-I Infections/blood , HTLV-I Infections/diagnosis , Proviruses , Cohort Studies , Paraparesis, Tropical Spastic/blood , Paraparesis, Tropical Spastic/immunology , Paraparesis, Tropical Spastic/virology , IncidenceABSTRACT
BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1), also denominated Human T-cell leukemia virus-1, induces immune activation and secretion of proinflammatory cytokines, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Regulatory T lymphocytes (Tregs) may control of inflammation through the production of regulatory cytokines, including IL10 and TGF-ß. In this study we determined the frequencies of CD4 + and CD8 + Tregs in a HAM/TSP population, compared to asymptomatic carriers and uninfected individuals, as well as investigated the profiles of regulatory and inflammatory cytokines. METHODS: Asymptomatic HTLV-1 carriers and HAM/TSP patients were matched by sex and age. The frequencies of IL10- and/or TGF-ß-producing Tregs were quantified by flow cytometry. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to quantify HTLV-1 proviral load and the mRNA expression of cytokines and cellular receptors in peripheral blood mononuclear cells. RESULTS: Total frequencies of CD4 + Tregs, as well as the IL10-producing CD4 + and CD8 + Treg subsets, were statistically higher in patients with HAM/TSP compared to asymptomatic HTLV-1-infected individuals. In addition, a positive correlation was found between the frequency of CD4 + IL10 + Tregs and proviral load in the HAM/TSP patients evaluated. A positive correlation was also observed between gene expression of proinflammatory versus regulatory cytokines only in HAM / TSP group. CONCLUSIONS: A higher frequencies of IL10-producing Tregs were identified in patients with HAM/TSP. Imbalanced production of IL10 in relation to TGF-ß may contribute to the increased inflammatory response characteristically seen in HAM/TSP patients.
Subject(s)
Human T-lymphotropic virus 1 , Interleukin-10 , Paraparesis, Tropical Spastic , T-Lymphocytes, Regulatory , Transforming Growth Factor beta , Humans , T-Lymphocytes, Regulatory/immunology , Male , Female , Paraparesis, Tropical Spastic/immunology , Paraparesis, Tropical Spastic/virology , Interleukin-10/immunology , Interleukin-10/genetics , Middle Aged , Human T-lymphotropic virus 1/immunology , Transforming Growth Factor beta/metabolism , Adult , Viral Load , Aged , HTLV-I Infections/immunology , HTLV-I Infections/virology , Carrier State/immunology , Carrier State/virologyABSTRACT
Recent studies have shown the effects of vitamin D on host response to infectious diseases. Some studies detected a high prevalence of hypovitaminosis D in HIV-infected patients, but scarce information exists for HTLV-1 infection. We conducted a cross-sectional study to evaluate the frequency of hypovitaminosis D in HTLV-1 patients and its relationship with their immune response in HTLV-infected patients and in age- and gender-matched controls at a Brazilian rehabilitation hospital. We compared vitamin D, interleukin-6 (IL-6), tumoral necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) levels across groups. Logistic regression was utilized to assess the association between hypovitaminosis D and cytokine levels. We enrolled 161 HTLV-infected subjects (129 HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, 32 asymptomatic HTLV carriers) and equal number of HTLV-negative controls. We observed a significantly higher prevalence of hypovitaminosis D in patients with HAM/TSP than in HTLV asymptomatic carriers (p < 0.001), or controls (p < 0.001). HAM/TSP patients also had higher levels of IL-6 and IFN-γ than asymptomatic carriers. Patients with HAM/TSP and hypovitaminosis D had higher levels of TNF-α than asymptomatic HTLV carriers. These findings suggest hypovitaminosis D plays a role in HAM/TSP pathogenesis, and it needs to be evaluated in further studies.
Subject(s)
Cytokines/blood , Paraparesis, Tropical Spastic/immunology , Vitamin D Deficiency/immunology , Adult , Aged , Brazil/epidemiology , Carrier State/epidemiology , Carrier State/immunology , Cross-Sectional Studies , Female , HTLV-I Infections/epidemiology , HTLV-I Infections/immunology , Human T-lymphotropic virus 1/pathogenicity , Humans , Inflammation , Male , Middle Aged , Paraparesis, Tropical Spastic/epidemiology , Prevalence , Vitamin D/blood , Vitamin D Deficiency/epidemiologyABSTRACT
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy of CD4+ T-cells associated with HTLV-1 infection. In this study, we used the model of immunodeficient NSG mice reconstituted with a functional human immune system (HIS) to investigate early events in HTLV-1 pathogenesis. Upon infection, human T-cells rapidly increased in the blood and lymphoid tissues, particularly CD4+CD25+ T-cells. Proliferation of CD4+ T-cells in the spleen and mesenteric lymph nodes (MLN) correlated with HTLV-1 proviral load and CD25 expression. In addition, splenomegaly, a common feature of ATLL in humans, was also observed. CD4+ and CD8+ T-cells predominantly displayed an effector memory phenotype (CD45RA-CCR7-) and expressed CXCR3 and CCR5 chemokine receptors, suggesting the polarization into a Th1 phenotype. Activated CD8+ T-cells expressed granzyme B and perforin; however, the interferon-γ response by these cells was limited, possibly due to elevated PD-1 expression and increased frequency of CD4+FoxP3+ regulatory T-cells in MLN. Thus, HTLV-1-infected HIS-NSG mice reproduced several characteristics of infection in humans, and it may be helpful to investigate ATLL-related events and to perform preclinical studies. Moreover, aspects of chronic infection were already present at early stages in this experimental model. Collectively, we suggest that HTLV-1 infection modulates host immune responses to favor viral persistence.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , HTLV-I Infections/virology , Human T-lymphotropic virus 1/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , HTLV-I Infections/immunology , Human T-lymphotropic virus 1/metabolism , Humans , Leukemia-Lymphoma, Adult T-Cell/immunology , Leukemia-Lymphoma, Adult T-Cell/pathology , Leukemia-Lymphoma, Adult T-Cell/virology , Leukocyte Common Antigens/metabolism , Mice , Persistent Infection/immunology , Persistent Infection/virologyABSTRACT
The impact of HIV co-infection on the plasma immunological biomarker profile of HTLV-1 infected patients was evaluated. The plasma levels of leukotrienes and chemokines/cytokines were quantified by ELISA and Cytometric Bead Array. A total of 138 volunteers were enrolled and divided into two subgroups ("HTLV-1(+)HIV(-)" and "HTLV-1(+)(HIV(+)"), which were categorized according to the HTLV-1-associated neurological disease (AS, pHAM and HAM). Reference controls were BD and HIV mono-infected patients. HAM(+) exhibited higher CD4+ T-cell counts as compared to HIV+ mono-infected patients and lower HTLV-1 proviral load as compared to mono-infected HAM(-) patients. AS(+) exhibited higher levels of CysLT, CXCL8/IL-8 and lower levels of CCL5/RANTES as compared to AS(-). Increased levels of IL-6 and TNF with reduced levels of CXCL10/IP10 and CCL5/RANTES were observed in co-infected pHAM(+) as compared to mono-infected pHAM(-). HAM(+) patients revealed an increase in CXCL8/IL-8, CCL2/MCP-1, CXCL-10/IP-10, TNF and a decrease in IL-2 as compared to HAM(-) subgroup.
Subject(s)
Coinfection , HIV Infections/immunology , HIV Infections/metabolism , HTLV-I Infections/immunology , HTLV-I Infections/metabolism , Host-Pathogen Interactions/immunology , Human T-lymphotropic virus 1/immunology , Adult , Biomarkers , CD4 Lymphocyte Count , Cross-Sectional Studies , Cytokines/blood , Cytokines/metabolism , Disease Susceptibility , Female , HIV Infections/virology , HTLV-I Infections/virology , Host-Pathogen Interactions/genetics , Humans , Leukotrienes/metabolism , Male , Middle Aged , Viral LoadABSTRACT
BACKGROUND: The forkhead box protein 3 (FOXP3) transcription factor is one of the main markers of immunological suppression in different pathological profiles, and the presence of polymorphic variants may alter the gene expression of this factor. Despite descriptions of an association between the presence of the rs2232365 polymorphism and chronic diseases, the role of the sex variant in this context has not yet been elucidated, as the FOXP3 gene is located on the human sex chromosome X. RESULTS: To contribute to this topic, 323 women and 373 men were enrolled in the study, of which 101 were diagnosed with chronic viral liver diseases (39 women and 62 men), 67 with HTLV-1 infection (44 women and 23 men), 230 with coronary artery disease (91 women and 139 men) and 298 healthy and uninfected blood donors (149 women and men). They were genotyped for the rs2232365 polymorphism. The rs2232365 polymorphism was associated with clinical and pathological aspects and biomarkers of viral infections only in men, with functional differences between different infections. CONCLUSIONS: A relationship is suggested between sex and FOXP3 rs2232365 polymorphism, resulting in different biological repercussions.
Subject(s)
Forkhead Transcription Factors/metabolism , Genotype , HTLV-I Infections/genetics , Human T-lymphotropic virus 1/physiology , Sex Factors , Adult , Case-Control Studies , Chronic Disease , Coronary Artery Disease/genetics , Female , Forkhead Transcription Factors/genetics , Genetic Predisposition to Disease , HTLV-I Infections/immunology , Humans , Male , Polymorphism, Single NucleotideABSTRACT
A high proviral load (PVL) is recognized as a risk factor for human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), but there is a lack of prospective studies evaluating whether or not HTLV-1 carriers with high PVL are at risk of developing HAM/TSP or other HTLV-1-related diseases. Here, we compare the incidence of clinical manifestations and the cytokine levels in 30 HTLV-1 carriers with high (> 50,000 copies/106 PBMC) and an equal number of subjects with low proviral load. Participants were followed for 3 to 16 years (median of 11 years). The PVL, IFN-γ, TNF, and IL-10 levels were quantified at entry and at the end of the follow-up. Among the self-reported symptoms in the initial evaluation, only the presence of paresthesia on the hands was more frequent in the group with high PVL (p < 0.04). The production of IFN-γ was higher in the group with high PVL group (median of 1308 versus 686 pg/ml, p < 0.011) when compared with the control group in the first assessment. There was no difference in the occurrence of urinary symptoms or erectile dysfunction, periodontal disease, Sicca syndrome, and neurologic signs between the two groups during the follow-up. The observation that none of the HTLV-1 carriers with high PVL and with exaggerated inflammatory response progressed to HAM/TSP indicates that other factors in addition to the PVL and an exaggerated immune response are involved in the pathogenesis of HAM/TSP.
Subject(s)
Carrier State/immunology , HTLV-I Infections/immunology , Human T-lymphotropic virus 1/immunology , Leukocytes, Mononuclear/immunology , Proviruses/immunology , Adult , Aged , Carrier State/diagnosis , Carrier State/virology , Erectile Dysfunction/diagnosis , Erectile Dysfunction/genetics , Erectile Dysfunction/immunology , Erectile Dysfunction/virology , Female , Gene Expression , HTLV-I Infections/diagnosis , HTLV-I Infections/genetics , HTLV-I Infections/virology , Human T-lymphotropic virus 1/growth & development , Humans , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Leukocytes, Mononuclear/virology , Longitudinal Studies , Male , Middle Aged , Nocturia/diagnosis , Nocturia/genetics , Nocturia/immunology , Nocturia/virology , Proviruses/growth & development , Sjogren's Syndrome/diagnosis , Sjogren's Syndrome/genetics , Sjogren's Syndrome/immunology , Sjogren's Syndrome/virology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Viral Load/immunologyABSTRACT
Human T-lymphotropic virus 1, a member of the Retroviridae family, causes a neglected, silent, persistent infection affecting circa 5 to 10 million people around the world, with biology, immune pathology, clinical diseases, epidemiology, and laboratory issues still unsolved. Most of the infected subjects are asymptomatic, but severe clinical disorders appear as a neurodegenerative disease (HTLV-1 associated myelopathy-HAM) or a lymphoprolipherative disorder (Adult T Leukemia/Lymphoma-ATLL) and in other target organs of the human body. HTLV-1 infections are frequently asymptomatic, but there is a large spectrum of diseases that have been described along the years. The mechanisms by which the virus interacts with the host, the different modes of response of the host to the infection, and the immunogenic characteristics of the host are some of the interesting and unanswered questions that may direct the outcome of the disease. The most relevant published results dealing with the genetic variations of the host, the immune response to HTLV-1 infection, and the outcome of the infection are presented herein, including Human Leucocyte Antigen (HLA), Killer Immunoglobulin-like Receptors (KIR), interleukin 6, 10, 28, Fas and Fas ligand, IFN-gamma, TNF-A, and Mannose-binding lectin. In summary, there are still several unmet research needs in the field of useful biomarkers on HTLV-1 pathogenesis.
Subject(s)
HTLV-I Infections/immunology , HTLV-I Infections/virology , Human T-lymphotropic virus 1/physiology , Animals , Biomarkers/blood , HTLV-I Infections/blood , Human T-lymphotropic virus 1/genetics , Humans , ImmunogeneticsABSTRACT
Human T-cell lymphotropic virus type-1 (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is a chronic inflammatory disease that leads to gradual loss of motor movement as a result of the death of spinal cord cells through immune mediated mechanisms. The risk to develop HAM/TSP disease positively correlates with the magnitude of HTLV-1 proviral load. Gamma-delta T lymphocytes have been recognized as important players in a variety of infectious diseases. Therefore, we have investigated interactions between HTLV-1 infection and γδ T lymphocytes during HAM/TSP. Similar frequencies of total γδ T lymphocytes and their Vγ9δ2+ and Vγ9δ2neg subpopulations were observed in HAM/TSP patients. However, T lymphocytes obtained from HTLV-1 carriers displayed significantly higher rates of spontaneous proliferation and NKp30 expression when compared to cells from uninfected donors. In addition, an important decrease in the frequency of granzyme B+ γδ T lymphocytes (approximately 50%) was observed in HAM/TSP patients. Higher proportion of IFN-γ+ γδ T lymphocytes was found in HTLV-1-infected patients, which positively correlated with the HTLV-1 proviral load in peripheral blood mononuclear cells. Collectively, our data indicates that HTLV-1 infection leads to phenotypic and functional changes in the population of γδ T lymphocyte population, suggesting that HTLV-1 infection modulates functions associated to these cells, which might be involved in controlling the infection or in the development of HTLV-1-associated diseases.
Subject(s)
Carrier State/immunology , Carrier State/virology , Human T-lymphotropic virus 1/physiology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , T-Lymphocytes/immunology , Cell Proliferation , Cytotoxicity, Immunologic , Granzymes/metabolism , HTLV-I Infections/immunology , HTLV-I Infections/virology , Humans , Interferon-gamma/biosynthesis , Lymphocyte Count , Phenotype , Proviruses/physiologyABSTRACT
BACKGROUND: Natural killer (NK) cells are part of the innate immune system and provide surveillance against viruses and cancers. The ability of NK cells to kill virus-infected cells depends on the balance between the effects of inhibitory and activating NK cell receptors. This study aimed to investigate the phenotypic profile and the functional capacity of NK cells in the context of HTLV-1 infection. METHODS: This cross-sectional study sequentially recruited HTLV-1 infected individuals with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and asymptomatic HTLV-1 (AS) from the Integrated and Multidisciplinary HTLV Center in Salvador, Brazil. Blood samples from healthy blood donors served as controls. NK cell surface receptors (NKG2D, KIR2DL2/KIR2DL3, NKp30, NKG2A, NKp46, TIM-3 and PD-1), intracellular cytolytic (Granzyme B, perforin) and functional markers (CD107a for degranulation, IFN-γ) were assayed by flow cytometry in the presence or absence of standard K562 target cells. In addition, cytotoxicity assays were performed in the presence or absence of anti-NKp30. RESULTS: The frequency of NKp30+ NK cells was significantly decreased in HAM/TSP patients [58%, Interquartile Range (IQR) 30-61] compared to controls (73%, IQR 54-79, p = 0.04). The production of cytolytic (perforin, granzyme B) and functional markers (CD107a and IFN-γ) was higher in unstimulated NK cells from HAM/TSP and AS patients compared to controls. By contrast, stimulation with K562 target cells did not alter the frequency of CD107a+ NK cells in HAM/TSP subjects compared to the other groups. Blockage of the NKp30 receptor was shown to decrease cytotoxic activity (CD107a) and IFN-γ expression only in asymptomatic HTLV-1-infected individuals. CONCLUSIONS: NK cells from individuals with a diagnosis of HAM/TSP present decreased expression of the activating receptor NKp30, in addition to elevated degranulation activity that remained unaffected after blocking the NKp30 receptor.
Subject(s)
Killer Cells, Natural/immunology , Natural Cytotoxicity Triggering Receptor 3/metabolism , Paraparesis, Tropical Spastic/immunology , Adult , Antibodies, Monoclonal/pharmacology , Biomarkers/metabolism , Cross-Sectional Studies , Female , Flow Cytometry , Granzymes/metabolism , HTLV-I Infections/immunology , HTLV-I Infections/virology , Humans , Interferon-gamma/metabolism , K562 Cells , Killer Cells, Natural/metabolism , Killer Cells, Natural/virology , Male , Middle Aged , Natural Cytotoxicity Triggering Receptor 3/antagonists & inhibitors , Paraparesis, Tropical Spastic/virology , Perforin/metabolismABSTRACT
The cytotoxic activities of CD8+ T cells have been considered the main defense mechanism against the human T lymphotropic virus type 1 (HTLV-1). As with CD8+ T cells, NK cells can perform cytotoxic degranulation with production of cytotoxic mediators, such as perforins and granzymes. NK cells are also responsible for antibody-dependent cellular cytotoxicity (ADCC) against infected cells, but few studies have evaluated the role of NK cells in HTLV-1 infection. The aim of this study was to characterize the subsets and measure the frequency of NK cells in HTLV-1 carriers (HC) and in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and correlate these findings with the proviral load and development of HAM/TSP. The diagnosis of HTLV-1 infection was performed with a detection antibody against viral antigens by ELISA and confirmed by Western blot. Phenotypic characterization of NK cells was performed by flow cytometry. The frequencies of CD56+, CD56+CD3-, CD56+CD16+, and CD56dim cells were decreased in HAM/TSP patients. The frequency of CD56+CD3- cells was inversely correlated with proviral load in HC but not in HAM/TSP patients. HAM/TSP patients showed decreased frequency of CD56+ and CD56dim cells expressing CD16, the main receptor for ADCC. These data indicate that NK cells may play a key role in the control of HTLV-1 infection by preventing the progression of HC to HAM/TSP.
Subject(s)
Carrier State/virology , HTLV-I Infections/immunology , Killer Cells, Natural/immunology , Paraparesis, Tropical Spastic/immunology , Viral Load , Adult , Aged , Antibody-Dependent Cell Cytotoxicity , Female , Flow Cytometry , HTLV-I Infections/complications , Human T-lymphotropic virus 1 , Humans , Killer Cells, Natural/classification , Lysosomal-Associated Membrane Protein 1/genetics , Lysosomal-Associated Membrane Protein 1/immunology , Male , Middle Aged , Young AdultABSTRACT
INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1) is sexually transmitted and causes persistent infection. This virus induces activation of the immune system and production of inflammatory cytokines. This study aimed to assess the cytokine profile and cytopathological findings in the cervicovaginal fluid of asymptomatic HTLV-1-infected women. METHODS: HTLV-1-infected and uninfected women were selected at the Centro de Atendimento ao Portador de HTLV in Salvador-Brazil. None of the included HTLV-1-infected women reported any HTLV-1-associated diseases. All volunteers underwent gynecological examination to collect cervicovaginal fluid. Cytokine quantification was performed using the Cytometric Bead Array (CBA) Human Th1/Th2/Th17 kit. Light microscopy was used to evaluate cervicovaginal cytopathology. In addition, proviral load in cervicovaginal fluid and peripheral blood was measured by real-time quantitative polymerase chain reaction. RESULTS: 112 women (63 HTLV-1-infected and 49 uninfected) were evaluated. No differences were found with respect to cytopathological cervicovaginal findings between the groups. IL-2, TNF, IL-4, IL-10, and IL-17 levels were significantly higher in cervicovaginal fluid of the HTLV-1-infected women than in uninfected women (p<0.05). Conversely, IFN-γ was found to be lower in the HTLV-1-infected women (p<0.001) compared to uninfected individuals. Cervicovaginal proviral load was detectable in 53% of the HTLV-1-infected women and was found to be consistently lower than the proviral load in peripheral blood. CONCLUSIONS: HTLV-1 infection induces immune activation in cervicovaginal environment, characterized by elevated concentrations of Th1, Th2, and IL17 in the cervicovaginal fluid.
Subject(s)
Body Fluids/chemistry , Cervix Uteri/pathology , Cytokines/analysis , HTLV-I Infections/pathology , Vagina/pathology , Adult , Body Fluids/immunology , Cervix Uteri/immunology , Cervix Uteri/virology , Cross-Sectional Studies , Enzyme-Linked Immunosorbent Assay , Female , HTLV-I Infections/immunology , HTLV-I Infections/virology , Human T-lymphotropic virus 1/isolation & purification , Humans , Interleukin-17/immunology , Leukocytes, Mononuclear/virology , Social Class , Statistics, Nonparametric , Th1 Cells/immunology , Th2 Cells/immunology , Vagina/immunology , Vagina/virology , Viral LoadABSTRACT
ABSTRACT Introduction: Human T-cell lymphotropic virus type 1 (HTLV-1) is sexually transmitted and causes persistent infection. This virus induces activation of the immune system and production of inflammatory cytokines. This study aimed to assess the cytokine profile and cytopathological findings in the cervicovaginal fluid of asymptomatic HTLV-1-infected women. Methods: HTLV-1-infected and uninfected women were selected at the Centro de Atendimento ao Portador de HTLV in Salvador-Brazil. None of the included HTLV-1-infected women reported any HTLV-1-associated diseases. All volunteers underwent gynecological examination to collect cervicovaginal fluid. Cytokine quantification was performed using the Cytometric Bead Array (CBA) Human Th1/Th2/Th17 kit. Light microscopy was used to evaluate cervicovaginal cytopathology. In addition, proviral load in cervicovaginal fluid and peripheral blood was measured by real-time quantitative polymerase chain reaction. Results: 112 women (63 HTLV-1-infected and 49 uninfected) were evaluated. No differences were found with respect to cytopathological cervicovaginal findings between the groups. IL-2, TNF, IL-4, IL-10, and IL-17 levels were significantly higher in cervicovaginal fluid of the HTLV-1-infected women than in uninfected women (p < 0.05). Conversely, IFN-γ was found to be lower in the HTLV-1-infected women (p < 0.001) compared to uninfected individuals. Cervicovaginal proviral load was detectable in 53% of the HTLV-1-infected women and was found to be consistently lower than the proviral load in peripheral blood. Conclusions: HTLV-1 infection induces immune activation in cervicovaginal environment, characterized by elevated concentrations of Th1, Th2, and IL17 in the cervicovaginal fluid.
Subject(s)
Humans , Female , Adult , Vagina/pathology , Body Fluids/chemistry , HTLV-I Infections/pathology , Cervix Uteri/pathology , Cytokines/analysis , Social Class , Vagina/immunology , Vagina/virology , Body Fluids/immunology , Enzyme-Linked Immunosorbent Assay , Leukocytes, Mononuclear/virology , Human T-lymphotropic virus 1/isolation & purification , HTLV-I Infections/immunology , HTLV-I Infections/virology , Cervix Uteri/immunology , Cervix Uteri/virology , Cross-Sectional Studies , Th2 Cells/immunology , Th1 Cells/immunology , Statistics, Nonparametric , Viral Load , Interleukin-17/immunologyABSTRACT
Human multipotent mesenchymal stromal cells (MSCs) display immunoregulatory functions that can modulate innate and adaptive cellular immune responses. The suppressive and immunomodulatory activities of MSCs occur through the action of soluble factors that are constitutively produced and released by these cells or, alternatively, after MSC induction by stimuli of inflammatory microenvironments. However, to date the contribution of MSCs in the inflammatory microenvironment resulting from viral infection is unknown. In our study, we evaluated the MSC immunosuppressive effect on human T lymphotropic virus type 1 (HTLV-1) infected T lymphocytes. To evaluate if MSC immunoregulation can influence the proliferation of HTLV-1 infected T lymphocytes, we compared the proliferation of lymphocytes obtained from HTLV-1 infected and healthy individuals cocultured in the presence of MSCs. It was observed that the lymphoproliferative inhibition by MSCs on infected lymphocytes was similar compared to the cells obtained from healthy individuals. In addition, this suppressive effect was related to a significant increase of indoleamine-2,3-dioxygenase and prostaglandin E2 gene expression (p ≤ .05). Furthermore, the HTLV-1 pol gene was less expressed after coculturing with MSCs, suggesting that the MSC immunoregulation can have effective suppression on HTLV-1 infected T cells. In conclusion, this study suggests that MSCs could be involved in the immunomodulation of the HTLV-1 infected T lymphocytes.
Subject(s)
HTLV-I Infections/immunology , Immunomodulation , Mesenchymal Stem Cells/immunology , T-Lymphocytes/immunology , Adult , Cell Differentiation , Cells, Cultured , Coculture Techniques , Female , Human T-lymphotropic virus 1/genetics , Humans , Lymphocyte Activation , Male , Middle Aged , T-Lymphocytes/virology , Viral Proteins/geneticsABSTRACT
BACKGROUND: HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is related with high proviral load, high proinflammatory cytokine levels, and passage of infected cell from the blood to the central nervous system. We aimed to evaluate the participation of chemokines and adhesion molecules in HAM/TSP pathogenesis. METHODS: CXCL9, CXCL10, sICAM-1, and sVCAM-1 were determined by ELISA in serum and cerebrospinal fluid (CSF) of HTLV-1 infected individuals. The frequency and median fluorescence intensity (MFI) of lymphocytes and monocytes expressing ligands of adhesion molecules (CD11a and CD49d) and a chemokine receptor (CXCR3) were analyzed by flow cytometry. RESULTS: The levels of CXCL9 and CXCL10 in serum of definite HAM/TSP were higher than in serum of probable HAM/TSP and HTLV-1 carriers. Considering the production of chemokines by patients with definite HAM/TSP, CXCL9 levels were higher in serum than in CSF, and CXCL10 production was higher in CSF than in serum. Levels of adhesion molecules in serum and CSF of HTLV-1 infected individuals did not differ. The MFI of CD11a on CD4+, CD8+ and CD14+ cells was lower in definite HAM/TSP than in HTLV-1 carriers and did not differ from probable HAM/TSP and healthy subjects (HS). The frequency of lymphocytes expressing CXCR3 was lower in definite HAM/TSP than in cells of probable HAM/TSP and did not differ from carrier and HS. CONCLUSION: These data point to the participation of proinflammatory chemokines, especially CXCL10, in the pathogenesis of definite HAM/TSP.
Subject(s)
Chemokines/immunology , Inflammation/immunology , Paraparesis, Tropical Spastic/immunology , Adult , Aged , Carrier State/immunology , Female , HTLV-I Infections/immunology , Human T-lymphotropic virus 1/immunology , Humans , Male , Middle Aged , Young AdultABSTRACT
Strongyloides stercoralis is the main etiological agent of human strongyloidiasis. Severe strongyloidiasis is commonly associated to alcoholism, corticostereoid use, and human T cell lymphotropic virus type 1 (HTLV-1) coinfection. Herein, we report a case of a 13-year-old boy coinfected with S. stercoralis and HTLV-1, excreting several parasitic forms in the stool. The parasitological examination of his feces showed a large amount of filariform (about 3,000 larvae per gram of feces) and rhabditiform larvae (about 2,000 larvae per gram of feces). In addition, free-living adult females (about 50 parasites per gram of feces) and eggs (about 60 eggs per gram of feces) were detected. The main laboratory findings pointed to high immunoglobulin E (IgE) levels (228 UI/mL) and eosinophila (11.6%). The patient was treated with three courses of ivermectin (200 µg/kg twice, 2 weeks apart), achieving the parasitological cure. An increase of about 19 times in interleucin (IL)-17 level was observed following the parasitological cure, in addition to a decrease in the white blood cell, eosinophil counts, and IgE levels. This is the first case report, to our knowledge, in which an S. stercoralis adult free-living female was described in human feces and where an increase in IL-17 levels after Strongyloides treatment in a HTLV-1 coinfected individual was observed. This finding raises the need for further studies about IL-17 immunomodulation in S. stercoralis and HTLV-1 coinfected patients.
Subject(s)
Feces/parasitology , HTLV-I Infections/diagnosis , Human T-lymphotropic virus 1/immunology , Strongyloides stercoralis/immunology , Strongyloidiasis/diagnosis , Adolescent , Animals , Anthelmintics/therapeutic use , Brazil , Coinfection , Female , HTLV-I Infections/immunology , HTLV-I Infections/pathology , Human T-lymphotropic virus 1/isolation & purification , Humans , Immunoglobulin E/biosynthesis , Interleukin-17/biosynthesis , Ivermectin/therapeutic use , Larva/immunology , Male , Parasite Egg Count , Strongyloides stercoralis/isolation & purification , Strongyloidiasis/drug therapy , Strongyloidiasis/immunology , Strongyloidiasis/pathology , Zygote/immunologyABSTRACT
BACKGROUND: Among the complex of HTLV-associated diseases, Sjögren's syndrome (SS) is one of the most controversial. This work aims to detect morphological and inflammatory alterations, including clues of the presence of HTLV-1, in minor salivary glands of patients with dryness symptoms. METHODS: We have assessed HTLV-1-seropositive patients (HTLV-1 group) and patients with SS (SS group). We used formalin-fixed, paraffin-embedded minor salivary gland tissue to evaluate the morphological aspects and, by means of immunohistochemistry, the presence of Tax protein, CD4, CD8 and CD20 cells. Additionally, viral particles and proviral load were analysed by PCR. RESULTS: The HTLV-1 group had the highest prevalence of non-specific chronic sialadenitis (85.71%; P = 0.017) and greater amount of T CD8+ cells. In the SS group, focal lymphocytic sialadenitis (80%; P = 0.017) prevailed, with a greater amount of B CD20+ . Both immunohistochemistry and PCR identified the Tax protein and its gene in the salivary glands of both groups and in similar proportions. CONCLUSION: The results indicate that HTLV-1-seropositive patients have different patterns of morphological/inflammatory alterations, suggesting a likely difference in the process of immune activation.
Subject(s)
HTLV-I Infections/pathology , Salivary Glands, Minor/pathology , Sjogren's Syndrome/pathology , Antigens, CD20/metabolism , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/pathology , Female , Gene Products, tax/metabolism , HTLV-I Infections/immunology , HTLV-I Infections/metabolism , Humans , Immunohistochemistry , Male , Middle Aged , Pilot Projects , Polymerase Chain Reaction , Salivary Glands, Minor/immunology , Salivary Glands, Minor/metabolism , Sialadenitis , Sjogren's Syndrome/immunologyABSTRACT
INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1)induces exaggerated Th1 responses, whereas atopy is associated with exacerbated Th2 responses. METHODS: Here, a cross-sectional study compared the prevalence of atopy in HTLV-1 carriers and HAM/TSP patients. It also compared the spontaneous cytokine production in HTLV-1-infected individuals. A retrospective cohort study evaluated the development of neurological manifestations in atopic and non-atopic carriers. RESULTS: Atopic HAM/TSP patients with high IFN-γ production exhibited higher IL-5 levels than non-atopic patients. Allergic rhinitis accelerated the development of Babinski signals and overactive bladders. CONCLUSIONS: Abnormal Th1 and Th2 responses coexist in HTLV-1-infected individuals and allergic diseases may worsen the clinical course of HTLV-1 infections.
Subject(s)
Cytokines/biosynthesis , HTLV-I Infections/complications , Hypersensitivity, Immediate/epidemiology , Nervous System Diseases/virology , Cohort Studies , Cross-Sectional Studies , Female , HTLV-I Infections/immunology , HTLV-I Infections/pathology , Humans , Hypersensitivity, Immediate/blood , Hypersensitivity, Immediate/immunology , Male , Middle Aged , Nervous System Diseases/immunology , Paraparesis, Tropical Spastic/complications , Paraparesis, Tropical Spastic/immunology , Paraparesis, Tropical Spastic/pathology , Retrospective StudiesABSTRACT
Abstract INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1)induces exaggerated Th1 responses, whereas atopy is associated with exacerbated Th2 responses. METHODS: Here, a cross-sectional study compared the prevalence of atopy in HTLV-1 carriers and HAM/TSP patients. It also compared the spontaneous cytokine production in HTLV-1-infected individuals. A retrospective cohort study evaluated the development of neurological manifestations in atopic and non-atopic carriers. RESULTS: Atopic HAM/TSP patients with high IFN-γ production exhibited higher IL-5 levels than non-atopic patients. Allergic rhinitis accelerated the development of Babinski signals and overactive bladders. CONCLUSIONS: Abnormal Th1 and Th2 responses coexist in HTLV-1-infected individuals and allergic diseases may worsen the clinical course of HTLV-1 infections.