Human T-cell Lymphotropic Virus Type 1 Infected Individuals Research Articles

Evaluation of antioxidant status and oxidative stress markers in HTLV-1 infected individuals: correlation with the severity of virus-induced complications.

Introduction. Human T-cell lymphotropic virus type 1 (HTLV-1), a well-known member of the retroviridae family, potentially causes serious outcomes including adult T-cell leukaemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM-TSP). Oxidative stress plays a key role in progression and clinical exacerbation of several chronic infections. We have previously shown a reduction in serum total antioxidant capacity (TAC) during HTLV-1 infection and this study was set out to investigate the reasons for TAC reduction.Hypothesis/Gap Statement. Oxidant/antioxidant imbalance during HTLV-1 infection may result from disruptions in oxidant levels or antioxidant defence system.Aim. This study aimed to analyse the key enzymes and oxidant molecules playing important roles in virus-induced oxidative stress.Methodology. We measured serum activities of the major antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) as well as serum concentrations of the main oxidant markers: nitric oxide (NO) and malondialdehyde (MDA). Totally 40 HTLV-1 infected patients and 40 healthy controls were enrolled in this study. The patient group consisted of chronic carriers and patients with HAM-TSP (N=20).Results. The current study found that serum levels of MDA and NO were significantly higher in patient groups particularly in HAM-TSP patients (P<0.05). In addition, a reductive trend was observed in the serum activities of CAT, SOD, and GPX in HTLV-1 infected patients compared with healthy controls (P<0.05).Conclusion. Reduced activities of CAT, SOD, and GPX antioxidant enzymes along with the observed elevated concentrations of oxidant molecules may contribute to oxidative stress and worse outcomes during HTLV-1 infection.

CD30 Characterizes Polylobated Lymphocytes and Disease Progression in HTLV-1-Infected Individuals.

Purpose: Although expression of CD30 is reported in a subset of adult T-cell leukemia/lymphoma cases, its clinicopathologic significance is poorly understood. We aimed to characterize CD30-positive cells and clarify their tumorigenic role in human T-cell lymphotropic virus type 1 (HTLV-1)-infected cells.Experimental Design: CD30-positive peripheral blood mononuclear cells from individuals with differing HTLV-1 disease status were characterized, and the role of CD30 signaling was examined using HTLV-1-infected cell lines and primary cells.Results: CD30-positive cells were detected in all samples examined, and the marker was coexpressed with both CD25 and CD4. This cell population expanded in accordance with disease progression. CD30-positive cells showed polylobation, with some possessing "flower cell" features, active cycling, and hyperploidy. CD30 stimulation of HTLV-1-infected cell lines induced these features and abnormal cell division, with polylobation found to be dependent on the activation of PI3K. The results thus link the expression of CD30, which serves as a marker for HTLV-1 disease status, to an active proliferating cell fraction featuring polylobation and chromosomal aberrations. In addition, brentuximab vedotin, an anti-CD30 monoclonal antibody conjugated with auristatin E, was found to reduce the CD30-positive cell fraction.Conclusions: Our results indicate that CD30-positive cells act as a reservoir for tumorigenic transformation and clonal expansion during HTLV-1 infection. The CD30-positive fraction may thus be a potential molecular target for those with differing HTLV-1 disease status. Clin Cancer Res; 24(21); 5445-57. ©2018 AACR.

Spinal cord hypometabolism associated with infection by human T-cell lymphotropic virus type 1(HTLV-1).

BackgroundHTLV-1 infection is endemic in Brazil. About 1 to 2% of the Brazilian population is estimated to be infected, but most infected HTLV-1 individuals do not know about their own infection, which favors the continuity of sexual and vertical virus transmission. In addition, HTLV-1 associated central nervous system diseases and their pathophysiologic mechanisms are not fully understood. This study aimed to evaluate the correlation of spinal cord metabolism, viral and inflammatory profiles with features of neurological presentation in HTLV-1 infected individuals.MethodologyThis is a cross-sectional study of a cohort including 48 HTLV-1 infected individuals clinically classified as asymptomatic-AG (N = 21), symptomatic-SG (N = 11) and HAM/TSP-HG (N = 16) and a nested case-control study with HTLV-1 infected individuals-HIG (N = 48) and HTLV-1 non infected controls-CG (N = 30) that had their spinal cord analysed by Positron Emission Tomography with 18F-Fluordeoxyglucose (18F-FDG PET/CT). HTLV-1 infected individuals had 18F-FDG PET/CT results analyzed with clinical and demographic data, proviral load, cytokines and chemokines in the blood and cerebrospinal fluid (CSF).Principal Findings18F-FDG PET/CT showed hypometabolism in the thoracic spinal cord in HTLV-1 infected individuals. The method had an accuracy of 94.4% to identify HAM/TSP. A greater involvement of the thoracic spinal cord was observed, although hypometabolism was also observed in the cervical spinal cord segment in HTLV-1 infected individuals. Individuals with HAM/TSP showed a pro-inflammatory profile in comparison to asymptomatic and symptomatic groups, with a higher level of Interferon-inducible T-cell alpha chemoattractant (ITAC/CXCL11), IL-6, IL-12p70 in the plasma; and ITAC, IL-4, IL-5, IL-8 (CXCL8) and TNF-alpha in the CSF. Using regression, thoracic spinal cord SUV (standardized uptake value) and CSF ITAC level were identified as the HAM/TSP predictors in the multivariate model.Conclusions18F-FDG PET/CT imaging showed spinal cord hypometabolism in most HTLV-1 infected individuals, even in the asymptomatic HTLV-1 group. Thoracic spinal cord hypometabolism and CSF-ITAC levels were identified predictors of HAM/TSP.SignificanceOur findings suggested that in most HTLV-1 infected individuals there was compromise of central nervous system (CNS) structures despite of the lack of clinical symptoms. To explain the found hypometabolism, the role of microcirculatory and metabolic factors in the pathogenesis of neurological diseases associated with HTLV-1 infection must be further investigated. It is paramount to evaluate the central nervous function and to compare the performance among HTLV-1 infected individuals considered asymptomatic to the uninfected controls.

Association of Tuberculosis Status with Neurologic Disease and Immune Response in HTLV-1 Infection

The human T cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 infected individuals have increased susceptibility to Mycobacterium tuberculosis infection but the influence of tuberculosis (TB) on the course of HTLV-1 infection is unknown. The aim of this study was to evaluate the influence of TB on immunological, virologic, and neurologic features of HTLV-1 infection. This is a retrospective analysis of individuals enrolled in a cohort study from an HTLV-1 clinic who were evaluated for past or latent tuberculosis (LTB) and classified clinically as HTLV-1 carriers, probable HAM/TSP and definite HAM/TSP. Spontaneous cytokine production (interferon-gamma [IFN-γ], tumor necrosis factor [TNF], and interleukin[IL]-10), serum chemokines (CXCL9 and CXCL10) and HTLV-1 proviral load were evaluated. Of 172 participants, 64 did not have histories of TB (TB- group), 81 had LTB and 27 had TB in the past (TB+ group). In the TB+ group, there was a higher frequency of HAM/TSP patients (35%) than in HTLV-1 carriers (10%) (OR = 3.8, p = .0001). HAM/TSP patients with histories of TB had higher IFN-γ/IL-10 and TNF/IL-10 ratios when compared with HAM/TSP patients without histories of TB. There were no differences in serum chemokine production and proviral load across TB groups stratified on HTLV-1 clinical status. In conclusion, TB may influence the development of HAM/TSP, and patients with these two diseases have an impairment in the modulation of immune response.

HTLV-1 infection interferes with immune responses to Mycobacterium tuberculosis antigens

Tuberculosis (TB) is still a major health problem. IFN-γ and TNF are critical cytokines in the control of Mycobacterium tuberculosis (Mtb) infection. It has already been demonstrated that human T cell lymphotropic virus type 1 (HTLV-1) infection leads to a spontaneous IFN- γ and TNF production, however HTLV-1 infected subjects possess a 2-4 fold increased risk of developing tuberculosis. Nevertheless, the immune mechanisms involved in this phenomenon are still unclear. The aim of this study was to evaluate immunological features of the association between HTLV-1/Mtb in order to better understand the events leading to higher susceptibility to TB observed in HTLV-1 infected subjects. This was a cross-sectional study evaluating four groups: healthy control (HC group), HTLV-1 infected subjects without TB (HTLV-1 group) or with TB (HTLV-1 + TB group), and individuals with only TB (TB group). TNF, IL-1β, and IL-17 levels were measured in supernatants of non-stimulated or PPD stimulated peripheral blood mononuclear cells (PBMCs) by ELISA. PBMCs from HTLV-1 infected individuals had a decrease (p<0.05) in TNF production following PPD stimulation (median 114.5 pg/ml, IQ range 47-189 pg/ml) compared to non-stimulated cells (202 pg/ml, IQ range 100-250 pg/ml). When we normalized the data to non-stimulated cells, IL-1β production following PPD stimulation by individuals in the HTLV-1 + TB group (3 pg/ml, IQ range 0-43 pg/ml) was lower (p<0.05) than in patients with TB (87 pg/ml, IQ range 14-151 pg/ml). Similarly, HTLV-1/Mtb co-infected individuals had lower (p<0.05) production of IL-17 (9 pg/ml, IQ range 0-41 pg/ml) when compared to TB patients (43 pg/ml, IQ range 13-150 pg/ml). Impairment in TNF, IL-1β, and IL-17 production upon stimulation with mycobacterial antigens may contribute to the higher susceptibility to Mtb infection observed in HTLV-1 infected subjects. Financial support: CNPq, CAPES.

Human bone marrow mesenchymal stromal cells exhibit suppressive effects on lymphocytes derived from HTLV-1 infected individuals

Human multipotent mesenchymal stromal cells (MSC) display immunoregulatory functions that can modulate innate and adaptive cellular immune responses. The suppressive and immunomodulatory activities of MSC occur by the action of soluble factors that are constitutively produced and released by these cells or alternatively, after induction of MSC stimuli in inflammatory microenvironments. During the infection by the human T cell lymphotropic virus-type 1 (HTLV-1) around 1-5% of the infected individuals will develop a chronic inflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, up to date it is unknown the contribution of the MSC in the inflammatory microenvironment resulting from this chronic disease. In this study, we evaluated the MSC immunosuppressive effect on HTLV-1 infected T lymphocytes. Assays using co-culture of MSC and HTLV-1+ T lymphocyte lineages resulted in a decrease of both tax gene expression and HTLV-1 p19 antigen. The reduction of the tax gene expression and the HTLV-1 p19 were at the same time associated with 1.7 fold increase of IL-6 secretion and a higher PGE2, IDO and VCAM-1 gene expression (p≤0.05). 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+ and healthy individuals co-cultured in the presence of MSC. It was observed that the lymphoproliferative inhibition by MSC on infected lymphocytes was similar compared to the cells obtained from healthy individuals. Additionally, this suppressive effect was related to a significant increase of IDO and PGE2 gene expression (p≤0.05). Furthermore, the HTLV-1 pol gene and p19 protein were less expressed after co-culturing with MSC, suggesting that the MSC immunoregulation is effective on HTLV-1 infected T cells. In conclusion, this study suggests that MSC could be involved in the immunomodulation of the HTLV-1 infected T lymphocytes. Financial Support: FAPESP, CNPq and FUNDHERP. Keywords: MSC, HTLV-1, immunoregulation, gene expression.

Serum total antioxidant capacity status of HTLV-1 infected patients.

Many aspects of the pathogenesis of Human T-cell lymphotropic virus type 1 (HTLV-1) still need further elucidations. Previous studies have indicated that oxidative stress occurs during infection with the other retrovirus, human immunodeficiency virus 1 (HIV-1). Similar results have been observed in some other chronic viral infections including hepatitis B(HBV) and hepatitis C(HCV). In order to reveal possible oxidative stress in HTLV-1-infected patients, we evaluated serum total antioxidant capacity (TAC) as an indicator of oxidative stress in these patients. Forty-four HTLV-1-seropositive individuals were included in this study, consisting of 12 symptomatic and 32 asymptomatic (carrier) cases. Controls consisted of 36 apparently healthy, HTLV-1-, HIV- and hepatitis-seronegative individuals. All symptomatic patients had HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Serum TAC levels in patients and healthy individuals were measured using aquantitative TAC assay. The antioxidant capacity in HTLV-1-seropositive cases was significantly reduced compared to control group (P=0.001). In addition, TAC was lower in patients with more than 5 years history of HAM/TSP compared to those with ≤5 years duration of the myelopathy (P=0.03). Our results show adepletion of TAC during HTLV-1 infection, which intensifies along with the disease progress. This finding indicates arole of the oxidative stress in pathogenesis of HTLV-1. These results may prompt further research to evaluate any possible therapeutic effect of antioxidant dietary supplements for HTLV-1 infected individuals.

NO EVIDENCE OF OSTEOPOROSIS IN YOUNG HTLV-1-INFECTED CARRIERS

Osteoporosis has been reported among Human T-cell Lymphotropic Virus type 1 (HTLV-1) infected aged patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) diagnosis. However, the association between osteoporosis and HTLV-1 infection remains unclear. This study aimed to evaluate the presence of bone disorders in young HTLV-1 asymptomatic individuals. A cross sectional study was carried out at the HTLV Reference Center in Salvador, Brazil. Forty-seven HTLV-1 infected asymptomatic and 108 healthy subjects aged between 20 to 45 years were included. Biochemical markers of bone metabolism were measured and bone mineral density (BMD) was determined at the femoral neck and at the lumbar spine (L1 -L4). Significant low BMD (Z-score &lt;-1 ) was found in HTLV-1 infected individuals (1.177 ± 0.103) compared to control subjects (1.225 ± 0.146). In logistics regression analysis HTLV-1 infected subjects were more likely to have low BMD (OR = 3.48; 95%CI 1.29- 9.43) adjusted for low education and body mass index (BMI). Osteoporosis (Z-score &lt;-2) was not found among HTLV-1-infected group. In conclusion, our results found a low BMD in patients infected with HTLV-1 compared to uninfected controls. However, osteoporosis was not observed. Further studies should be conducted to evaluate the relationship between HTLV-1-infection and low BMD.

Prevalence and influence of tuberculosis in the neurologic manifestations of the Human T cell lymphotropic virus type 1 (HTLV-1)

HTLV-1 infects mainly T cells, leading to activation and cellular proliferation with exaggerated production of pro-inflammatory cytokines. The majority of HTLV-1 infected patients are considered as HTLV-1 carriers, but 5% will develop HTLV-1 associated myelopathy (HAM) and about 15% overactive bladder, an oligosymptomatic form of HAM. HTLV-1 is associated with increased susceptibility to Mycobacterium tuberculosis infection but up to now it is unknown if HTLV-1 influences the severity of tuberculosis and if tuberculosis may influence the outcome of HTLV-1. The aims of this study were to determine the prevalence and severity of tuberculosis (TB) in HTLV-1 infected patients and analyze whether TB influences the outcome of HTLV-1 infection. This is a cross-sectional study, in which the prevalence of tuberculosis was analyzed in 166 HTLV-1 infected individuals. Cytokine productions were determined by ELISA, the proviral load was evaluated by PCR. Tuberculosis occurred in 33 (22%) of cases and 70 (42%) had a positive tuberculin skin test (TST) (latent tuberculosis). The majority of the cases did not have severe tuberculosis. There was no difference in the proviral load, but there was a higher frequency of HAM/TSP in the group with tuberculosis than in HTLV-1 infected subjects without TB (P<0.05). This study shows that the prevalence of M.tuberculosis infection is 6 fold higher in HTLV-1 infected individuals than that described in the Brazilian population the majority of co-infected had latent tuberculosis and HTLV-1 may influence progression from infection to HAM/TSP.

Impairment of humoral and cellular immune response to tetanus toxoid in HTLV-1 infected individuals

The human T cell lymphotropic virus type-1 (HTLV-1) infect mainly T cells, dendritic cells and macrophages inducing T cell proliferation and increasing production of chemokines and cytokines by peripheral blood mononuclear cells (PBMC). However, as HTVL-1 may modify the immune response to other infectious agents, the aim of this study was to evaluate the humoral and cellular immune response before and after vaccination with tetanus toxoid (TT). Participants included 14 HTLV-1 carriers and 12 healthy subjects (HS). These individuals were immunized with two doses of tetanus toxoid vaccine. Antibodies to TT were determined by ELISA and the frequency of T cells expressing cytokines as well as the frequency of monocytes expressing co-stimulatory molecules were determined by FACS. The IgG titers anti-TT increased after immunization in both groups (p = 0.001), but HTLV-1 patients had lower levels of IgG anti-TT after immunization when compared with HS (p = 0.007). The frequency of CD4+ T cells expressing IFN-g, TNF and IL-10, after stimulation with TT, was lower in HTLV-1 infected subjects than the HS after immunization (p < 0.05). TNF and IL-12 expression by monocytes after stimulation with TT were higher in the HTLV-1 group than in HS. However there was an impairment in the HLA-DR expression by monocytes from HTLV-1 infected subjects. These results indicate that HTLV-1 infected subjects have a decreasing in humoral response and an impairment in both antigen presenting cells and T cell functions to a biased antigen. Financial Support: INCT-DT, CNPq, NIH R01.

High Prevalence of Skin Disorders among HTLV-1 Infected Individuals Independent of Clinical Status

BackgroundHuman T-cell lymphotropic virus type 1 (HTLV-1) infection can increase the risk of developing skin disorders. This study evaluated the correlation between HTLV-1 proviral load and CD4+ and CD8+ T cells count among HTLV-1 infected individuals, with or without skin disorders (SD) associated with HTLV-1 infection [SD-HTLV-1: xerosis/ichthyosis, seborrheic dermatitis or infective dermatitis associated to HTLV-1 (IDH)].MethodsA total of 193 HTLV-1-infected subjects underwent an interview, dermatological examination, initial HTLV-1 proviral load assay, CD4+ and CD8+ T cells count, and lymphproliferation assay (LPA).ResultsA total of 147 patients had an abnormal skin condition; 116 (79%) of them also had SD-HTLV-1 and 21% had other dermatological diagnoses. The most prevalent SD-HTLV-1 was xerosis/acquired ichthyosis (48%), followed by seborrheic dermatitis (28%). Patients with SD-HTLV-1 were older (51 vs. 47 years), had a higher prevalence of myelopathy/tropical spastic paraparesis (HAM/TSP) (75%), and had an increased first HTLV-1 proviral load and basal LPA compared with patients without SD-HTLV-1. When excluding HAM/TSP patients, the first HTLV-1 proviral load of SD-HTLV-1 individuals remains higher than no SD-HTLV-1 patients.ConclusionsThere was a high prevalence of skin disorders (76%) among HTLV-1-infected individuals, regardless of clinical status, and 60% of these diseases are considered skin disease associated with HTLV-1 infection.

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.

Increased Frequency of HTLV-1 Tax Specific CD8+ Regulatory T-Cells in HTLV-1 Infected Individuals.

Abstract 3676Poster Board III-612Regulatory T-cells (Tregs) mediate self-tolerance and moderate the immune response to various antigens. Their frequency and suppressive function are reduced in various autoimmune diseases like type 1 diabetes mellitus, systemic lupus, and rheumatoid arthritis, but may be excessive in certain malignancies. The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus with myriad clinical manifestations, most notably adult T-cell leukemia/lymphoma (ATLL) and HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP). We have previously described the decreased frequency and function of HTLV-1 specific CD8+ T-cells in ATLL patients compared to asymptomatic carriers (ACs) and healthy controls (HCs). We have also reported the relative exhaustion of HTLV-1 specific cytotoxic T-lymphocytes (CTLs) compared to cytomegalovirus (CMV)-specific CTLs in ACs, as demonstrated by upregulation of the co-inhibitory molecule, programmed death 1 (PD-1). Recent evidence supports the existence of CD8+ Tregs in humans, defined primarily by forkhead box P3 (FOXP3) transcription factor expression. Although a classic Treg phenotypic marker, FOXP3's aberrant expression makes it a less reliable marker in the setting of ATLL. Low expression or absence of interleukin 7 receptor (IL-7R) (CD127lo/-) on CD25+ T-cells has provided a useful alternative Treg phenotype, allowing preservation of cell viability for functional assays. Existing studies have focused mostly on CD4+ Tregs and a few on CD8+ Tregs in malignancy, but little is known about their involvement in the persistence of chronic viral infections like HTLV-1. In chronic HTLV-1 infection, FOXP3+CD25+ and CD127lo/-CD25+ Tregs comprise 8.3±4.6% and 8.1±4.3% of overall CD8+ T-cells, respectively (n=14). Expression of the FOXP3+CD25+ phenotype in CD8+ T-cells had a tendency towards correlation with the CD127lo/-CD25+ phenotype (r=0.561, p=0.073, n=11). Among ACs, we observed the CD127lo/-CD25+ Treg phenotype in HTLV-1 Tax-specific CD8+ T-cells (45±16.5%, n=8), which was significantly greater than CMV-specific CD8+ Tregs (25±15.8%, n=6) (p<0.05, Figure 1), as characterized by phycoerythrin-labelled HLA-A*2402 Tax301-309 or HLA-A*0201 Tax11-19 and HLA-A*24/ HLA-A*02 CMV tetramers respectively. We have demonstrated that the CD8+CD127lo/-CD25+ phenotype could be an alternative marker of CD8+ Tregs. These observations suggest that HTLV-1 specific CD8+ Tregs could be implicated in the impaired clearance of HTLV-1 infected and transformed cells. This surrogate marker may facilitate further exploration of the immunological significance of antigen specific CD8+ Tregs in chronic viral infection. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Higher Rate of Major Depression among Blood Donor Candidates Infected with Human T-Cell Lymphotropic Virus Type 1

Viral infections have been previously associated with psychiatric disorders. This work aimed to study the relationship between the human T-cell lymphotropic virus type 1 (HTLV-1) and depression. A case-control study with prevalent cases was conducted from April 2004 to June 2005. Participants were from a public transfusion center in Belo Horizonte, Brazil. The base population was composed of blood donor candidates infected with HTLV-1 (asymptomatic carriers), followed-up in a cohort study. As a control group, HTLV-1 seronegative blood donors were selected in a random fashion. Study participants underwent psychiatric evaluation using a structured diagnostic instrument, the Mini International Neuropsychiatry Interview (MINI), to estimate the rate of depression. The interviewer was unaware of participants' HTLV-1 serostatus. The co-variables studied were gender, age, formal education, personal income, and the presence of other psychiatric diagnoses. Logistic regression was used to examine the relation between HTLV-1 infection and depression. The final sample was composed of 74 individuals infected with HTLV-1 and 24 uninfected controls. The rate of depression was significantly higher in HTLV-1 carriers when compared with controls (39% vs. 8%; p-value = 0.005). HTLV-1 infection was independently associated with depression (OR = 6.17; CI 95% = 1.32-28.82). The results showed a higher rate of depression in HTLV-1 infected individuals. It was not possible to determine whether depression was related to knowledge of chronic retroviral infection or related to a biological effect of the retroviral infection.

Prevalence Ratio of HTLV-1 in Nursing Mothers From the State of Paraíba, Northeastern Brazil

The human T-cell lymphotropic virus type 1 (HTLV-1) was the first human retrovirus known as a direct causal agent of a malignant disease. The vertical route of HTLV transmission is the most frequent pathway of the virus contamination. This study was performed to determine the prevalence ratio of HTLV-1 infection among nursing women. From January 2004 to January 2005, blood samples from 1033 nursing mothers from Paraíba, Brazil were evaluated for HTLV antibodies by ELISA and HTLV-1 viral particles confirmed by polymerase chain reaction (PCR). HTLV antibodies were detected in 7 women. The overall seroprevalence ratio was 0.68% and HTLV-1 viral sequences were confirmed by PCR in 2 women. These preliminary data suggest that HTLV screening should be introduced as a mandatory test before breastfeeding and breast milk donation in Paraíba, Brazil. Additionally, counseling programs would help reduce the prevalence ratio of HTLV-1 infected individuals in this Brazilian region.

Flow cytometry evaluation of the T-cell receptor Vβ repertoire among human T-cell lymphotropic virus type-1 (HTLV-1) infected individuals: Effect of interferon alpha therapy in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

Human T-cell lymphotropic virus type-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is chronic inflammatory disease of the spinal cord characterized by perivascular lymphocytic cuffing and parenchymal lymphocytic infiltration. In this study using flow cytometry, we have investigated the T-cell receptor (TCR) Vβ repertoire of peripheral blood T lymphocytes in 8 HAM/TSP patients, 10 HTLV-1 infected healthy carriers, and 11 uninfected healthy controls to determine if there is a biased usage of TCR Vβ. We found that TCR Vβ7.2 was under-utilized and Vβ12 was over-utilized in CD4 + T cells of HTLV-1 infected individuals compared with healthy uninfected controls, whereas there were no such differences in CD8 + T cells. Comparison of Vβ repertoire changes before and after interferon-alpha (IFN-α) treatment for HAM/TSP revealed that one out of five patients showed dramatic decrease of specific Vβ in CD8 + T cells. Our results suggest that dominant Vβ subpopulations in CD4 + T cells evolved associated with chronic HTLV-1 infection, and IFN-α treatment for HAM/TSP does not induce a specific pattern of TCR Vβ changes.

ApaI polymorphism of vitamin D receptor gene is associated with susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis in HTLV-1 infected individuals

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is one outcome of human T-cell lymphotropic virus type-1 (HTLV-1) infection. It remains unknown why the majority of infected people remain healthy, whereas only approximately 2–3% of infected individuals develop the disease. The active form of vitamin D has immunomodulatory effects, and allelic variants of the vitamin D receptor (VDR) appear to be associated with differential susceptibility to several infectious diseases. To investigate whether VDR single nucleotide polymorphisms (SNPs) are associated with the development of HAM/TSP, we studied four VDR SNPs in a group of 207 HAM/TSP patients and 224 asymptomatic HTLV-1 seropositive carriers (HCs) in Kagoshima, Japan, by using PCR-RFLP analysis. We found that ApaI polymorphism of VDR is associated with the risk of HAM/TSP, although this polymorphism did not affect the provirus load of HTLV-1 in either HAM/TSP patients or HCs.