Human T-cell Lymphotropic Virus Type 1 Carriers Research Articles

Cognitive deficits in HTLV-1 patients.

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus known to be associated with adult T-cell lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Previous researches and brain imaging techniques have suggested cognitive abnormalities as well as brain damage in individuals infected with this virus. Given the insufficient amount of studies on how this virus can impact the affected person's cognition, we aimed to assess and compare the cognitive abnormalities of HAM/TSP patients, asymptomatic HTLV-1 carriers, and healthy controls. This cross-sectional study was conducted on 51 patients divided into 3 groups; a group of HAM/TSP patients, a group of asymptomatic HTLV-1 carriers, and an uninfected control group. Each group contained 17 members. The cognitive state of the studied population was assessed using the Mini-Mental State Exam (MMSE), Symbol Digit Modalities Test (SDMT), Rey-Osterrieth complex figure test (ROCF), the "Verbal Fluency Test" and the "Trail Making Test" (TMT) components of the Delis-Kaplan executive function system (D-KEFS) test, the Rey Auditory Verbal Learning Test (RAVLT), and digit span memory test. Patients diagnosed with HAM/TSP received significantly lower scores on the SDMT, ROCF, TMT, RAVLT, digit span memory test, and the orientation, calculation, and recall component of the MMSE assessment (p-value < 0.001). In addition, the asymptomatic HTLV-1 carriers obtained lower scores on the SDMT, ROCF, digit span memory test, and the orientation, calculation, and recall component of the MMSE assessment compared to the control group (p-value < 0.001). Overall, the findings suggest that HAM/TSP, or an asymptomatic infection with HTLV-1 could lead to cognitive deficits in the affected individuals. This can further emphasize the importance of assessing the cognitive function and psychiatric abnormalities of those infected with this virus.

Dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth in ATL.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4+ T cells caused by human T-cell lymphotropic virus type 1 (HTLV-1)-induced T-cell transformation. After infection with HTLV-1, it takes several decades for HTLV-1 carriers to develop ATL. The prognosis of ATL remains poor despite several new agents being approved in the last few years. Recently, it has been noted that epigenetic abnormalities, both DNA methylation and trimethylation at histone H3Lys27 (H3K27me3), contribute to ATL leukemogenesis. Here, we investigated the effect of combination treatment with DNA demethylating agents (azacitidine [AZA], decitabine (DAC), and OR-2100 (OR21), which is a silylated derivative of DAC) and inhibitors of enhancer of zeste homolog 2 (EZH2) (EPZ-6438 and DS-3201b), which catalyze trimethylation of H3K27, in ATL. The combination of DAC and OR21 but not AZA with EZH inhibitors exhibited synergistic anti-ATL effects invitro and invivo, concomitant with DNA demethylation and reduction of H3K27me3. The combination induced gene expression reprogramming. Dual-specificity phosphatase 5 (DUSP5), an extracellular signal-regulated kinase (ERK)-specific phosphatase, was identified as a key molecule that mediated the inhibitory effect of combination treatment by inactivating the ERK signaling pathway. DUSP5 was downregulated by DNA methylation and H3K27me3 accumulation in the promoter region in HTLV-1-infected cells from patients with ATL during ATL leukemogenesis. The present results demonstrate that dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth by restoring DUSP5, and that dual targeting of aberrant DNA and histone methylation is a feasible therapeutic approach for ATL.

Making Visible HTLV Infection in a Non-endemic Area of Argentina.

In Argentina, the human T-cell lymphotropic virus type 1 (HTLV-1) infection has been documented mainly among blood banks with a prevalence of ~0.02–0.046% for Buenos Aires city, 0.8% for the northeast, and 1% for the northwest; both areas are considered endemic for HTLV-2 and 1, respectively. Policies and specific guidelines for testing blood donors for HTLV are included since 2005. Screening for antibodies is performed at blood banks and confirmatory testing is performed at reference laboratories. There are no specific recommendations for the assistance of communities and individuals affected, nor referral to specialized clinics on the HTLV infection. In 2016, as a strategy of intervention, we opened a specialized clinical attendance in a referral infectious diseases public hospital for the comprehensive approach to patients with HTLV, offering follow-up and counseling for patients and their families for the early diagnosis of HTLV-1/2 and related diseases. During the study, 124 patients with presumptive HTLV positive diagnosis from blood bank, symptomatic patients (SPs), relatives, and descendants visited the unit. A total of 46 patients were HTLV positive (38 HTLV-1 and 8 HTLV-2). There were nine SPs (2 adult T-cell leukemia/lymphoma [ATL] and 7 HTLV-1-associated myelopathy/tropical spastic paraparesis [HAM/TSP]). All patients with HTLV-1 and−2 were offered to study their relatives. Two out of 37 (5.4%) descendants tested were positive for HTLV-1. Sexual partners were studied; among 6 out of 11 couples (54.5%) were found positive (5 HTLV-1 and 1 HTLV-2). Other relatives, such as mothers (1/2) and siblings (1/6), were positive for HTLV-1. According to the place of birth among HTLV-1 carriers, 58% were born in an endemic area or in countries where HTLV infection is considered endemic while for HTLV-2 carriers, 12.5% were born in an endemic area of Argentina. The proviral load (pVL) was measured in all, patients with HTLV-1 being higher in symptomatic compared with asymptomatic carriers. In addition, two pregnant women were early diagnosed during their puerperium and breastmilk replacement by formula was indicated. Inhibition of lactation was also indicated. Our study provides tools for a multidisciplinary approach to the infection and reinforces the importance of having specialized clinical units in neglected diseases, such as HTLV for counseling, clinical and laboratory follow-up, and providing useful information for patients for self-care and that of their families.

Outcomes of HTLV-1 Carriers with Diffuse Large B-Cell Lymphoma: A Single-Center Retrospective Matched Cohort Study

BackgroundThe human T-cell lymphotropic virus type 1 (HTLV-1) is associated with aggressive diseases, such as adult T-cell leukemia/lymphoma (ATLL). However, less is known on the impact of HTLV-1 infection in non-ATLL hematologic malignancies. We aimed to investigate if HTLV-1 carriers with diffuse large B-cell lymphoma (DLBCL) have worse survival outcomes than non-HTLV-1 carriers. Materials and MethodsWe performed a single-center retrospective cohort study by matching HTLV-1 carriers to non-carriers based on age, sex, Ann Arbor stage, and year of diagnosis. Our outcomes of interest were overall survival (OS) and progression-free survival (PFS). The Kaplan-Meier method was used to estimate OS and PFS between carriers and non-carriers. We fitted multivariate Cox regression models to assess the mortality and recurrence/disease progression risk of HTLV-1 infection. ResultsA total of 188 patients, 66 with HTLV-1 infection and 122 without HTLV-1, were included in the study. HTLV-1 carriers had higher extranodal involvement than non-carriers (47% vs. 27%, P = .010). With a median follow-up of 78 months (95% CI: 41-90 months), HTLV-1 carriers had a similar 5 year OS (41% vs. 42%, P = .940) and PFS (34% vs. 32%, P = .691) compared to non-carriers. In the multivariate Cox analysis, HTLV-1 infection was not associated with worse OS (aHR: 0.98, 95% CI: 0.64-1.50) or PFS (aHR: 0.90, 95% CI: 0.60-1.34). ConclusionHTLV-1 carriers with DLBCL did not have worse survival outcomes compared to non-carriers. Our results suggest that clinicians should follow standard guidelines for DLBCL management on HTLV-1 seropositive patients.

A significant association between CXCL10 -1447 A > G and IL18 -607 C > A gene polymorphism with human T-cell lymphotropic virus type 1 associated myelopathy/tropical spastic paraparesis (HAM-TSP), a case-control report from city of Mashhad, Iran.

Human T-cell lymphotropic virus type 1 (HTLV-1) is the first isolated retrovirus from humans, and 2-3% of infected individuals suffer from HTLV-1 associated myelopathy tropical spastic paraparesis (HAM-TSP). Previous studies indicated that the risk of HAM-TSP could be correlated with the individuals' genetic alterations. Mashhad is one of the areas infected with HTLV-1 in Iran. This study designed to examine the association between several important gene polymorphisms and HAM-TSP. Genotypes of 232 samples from controls, HTLV-1 carriers, and HAM-TSP patients were examined for FAS-670 (A > G), CXCL10-1447 (A > G), Foxp3-3279 (C > A), IL-18 -137 (C > G), and IL-18 -607 (C > A) gene polymorphisms by different polymerase chain reaction (PCR) techniques. A non-significant association was observed between FAS-670 A > G, Foxp3-3279 C > A, and IL-18 -137 C > G gene polymorphisms and HAM-TSP. Nevertheless, a significant (P<0.001) association between CXCL10-1447 A > G and IL-18 -607 C > A gene polymorphisms with HAM-TSP was observed in our study population. As previous studies revealed that the CXCL10 level in the cerebrospinal fluid of HAM-TSP patients was associated with the disease progression, and as we noticed, a direct association was observed between CXCL10-1447 A > G polymorphism and HAM-TSP. These polymorphisms might be recommended as a valuable prediction criterion for the severity of the disease. The contradiction between our findings and other studies regarding IL-18 -607 C > A gene polymorphism might be associated with various factors such as genotypes frequency in diverse races and population heterogeneity in the city of Mashhad.

Comprehensive genomic analysis identifying heterogeneity in peripheral T‐cell lymphoma

Peripheral T‐cell lymphoma (PTCL) is a heterogeneous entity generally with a poor prognosis. Recent genomic analyses have characterized genomic alterations and described gene expression profiling and epigenetic mechanisms in PTCL, leading to reveal molecular pathophysiology in detail. One of several important findings is that heterogeneities exist in both the disease and in individuals. Among PTCL subtypes, adult T‐cell leukemia/lymphoma (ATLL) and peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) are common in Japan. ATLL is an incurable T‐cell malignancy induced by human T‐cell lymphotropic virus type 1 (HTLV‐1). The global genomics of ATLL can be summarized as alterations involving T‐cell receptor (TCR) signaling and immune escape mechanisms. This highlights the fact that ATLL is a viral‐mediated T‐cell malignancy. Interestingly, several previous studies have found that the genomics of ATLL differ according to geographical region and age at diagnosis, suggesting disease heterogeneity, though they share HTLV‐1 infection as initial disease hit. Clonal expansion of the cells acquired by somatic mutations in ATLL‐related genes is identified in a part of HTLV‐1 carriers who developed ATLL later. The risk for ATLL may be updated based on findings in detail. PTCL‐NOS is a heterogeneous disease type of T‐cell lymphoma that does not correspond to any other type of PTCL. Several studies have stratified PTCL‐NOS according to transcriptional, genomic, microenvironmental, and clinical aspects. These kinds of analysis from multiple aspects are useful to understand the heterogeneous group. These efforts will help guide suitable translational research to target PTCL.

Clinical Features and Outcome of HTLV-1 Carriers Diagnosed with Hodgkin Lymphoma in Peru: A Matched Cohort Study

Background: The human T-cell lymphotropic virus type 1 (HTLV-1) is an oncogenic retrovirus that affects CD4+ T-cell lymphocytes and is the cause for adult T-cell leukemia/lymphoma (ATLL), an aggressive peripheral T-cell neoplasm. Hodgkin-like ATLL subtype is a unique entity usually indistinguishable from Hodgkin lymphoma (HL) in the setting of HTLV-1 infection. HTLV-1 proviral integration and TCR Cb1 gene rearrangement testing are often necessary to differentiate both entities. However, less is known on HTLV-1 carriers diagnosed with HL (HTLV-1+ HL). We aim to compare survival outcomes between HTLV-1+ HL and matched controls treated at the National Cancer Institute in Peru. Methods: We reviewed medical records of patients diagnosed and managed for HL at the National Cancer Institute (Instituto Nacional de Enfermedades Neoplasicas, INEN) in Lima-Peru between 2002 and 2019. All patients should have had serologic evaluation for HTLV-1 infection at the time of diagnosis and should have had no suspicion (or confirmation) of a T-cell neoplasm during pathological examination. To investigate the impact of HTLV-1 infection on survival, we matched HTLV-1+ HL cases to HTLV-1-negative HL patients (controls) based on age, sex, cancer staging, and comorbidities. Treatment responses were assessed according to the Lugano criteria. Survival curves (event-free and overall survival) were estimated using the Kaplan-Meier method and compared with the Log-rank test. Multivariate Cox regression analysis was fitted and reported as Hazard Ratios (HR) with a 95% confidence interval (95% CI). Results: A total of 68 HL patients were identified and had sufficient data for analysis. Twenty cases had HTLV-1+ HL and 48 HTLV-1-negative HL. Table 1 summarizes the clinical features and outcomes of HL patients. In all patients the median age at diagnosis was 55 years with a female/male ratio of 1:1. Histological subtypes of HL were not statistically different among both groups with mixed cellularity as the most common subtype (HTLV-1+ HL 50% vs. HTLV-1-negative HL 38%), followed by nodular sclerosis (HTLV-1+ HL 15% vs. 31%), lymphocyte-rich (HTLV-1+ HL 15% vs. 15%), and nodular lymphocyte-predominant (HTLV-1+ HL 5% vs. 4%). ECOG performance status ≤2, advanced-stage disease (III-IV), presence of B symptoms, and presence of extranodal disease at the time of diagnosis were not different in both groups. Co-infections were presented in 5 (7.4%) HL patients (1 strongyloidiasis and 3 tuberculosis in the HTLV-1+ HL group, and 1 tuberculosis in the HTLV-1 negative HL group). All HTLV-1-negative HL patients were treated with first-line ABVD regimen compared to 18 (90%) HTLV-1+ HL patients; the remaining HTLV-1+ HL patients received involved-field radiation (n=1) and best supportive care (n=1). HTLV-1+ HL patients had inferior response rates (complete and partial response) compared to the matched control group (CR: 60% vs. 71%, and PR: 15% vs. 27%, respectively, p=0.015). At a median follow-up of 5-years, the overall survival was 55% in HTLV-1+ HL versus 67% in the matched control group (aHR: 1.39, 95%CI [0.6-3.4], p=0.47) (Figure 1). In the multivariate analysis, HTLV-1 infection was not a significant prognostic factor for worse event-free or overall survival. Relapsed rates were not different between both groups (HTLV-1+ HL 25% vs. 20.8%), however, more deaths were seen in the HTLV-1+ HL group (60% vs. 35%) but this was not statistically significant. Conclusion: To the best of our knowledge, this is the first case series describing the characteristics and outcome of HTLV-1 carriers diagnosed with HL. We found lower response rates to conventional treatment in HTLV-1+ HL patients compared to HTLV-1 negative individuals. However, long-term outcomes and relapsed rates were not different among groups. Further investigation is needed to confirm the potential impact of HTLV-1 infection in HL outcome. Disclosures No relevant conflicts of interest to declare.

Comparative study of impulsiveness and risk behaviors among infected individuals with hepatitis C virus and human T-cell lymphotropic virus type 1

Introduction and objectivesHepatitis C virus (HCV) and human T-cell lymphotropic virus type 1 (HTLV-1) infections have chronic courses. HCV is primarily transmitted via the hematogenous route, whereas HTLV-1 is primarily transmitted sexually, although it can also be transmitted by blood. Individuals chronically infected with either HTLV-1 or HCV can differ in terms of behavioral characteristics and personality traits. This study compared the occurrence of risk behaviors and impulsivity aspects between HCV and HTLV-1 carriers. Materials and methodsObservational, comparative and cross-sectional study that involved a sample of outpatients who had HCV or HLTV-1, by way of a sociodemographic and behavioral questionnaire and the Barratt Impulsiveness Scale – BIS-11. 143 individuals with HCV and 113 individuals with HTLV-1 were evaluated. ResultsThere was a difference with regards to gender among patients, with mostly males affected in the HCV group. Risk behaviors commonly mediated by impulsiveness were significantly more frequent in the HCV group. Similarly, overall impulsiveness and domain nonplanning were higher in the HCV group. Multivariate analysis showed that increased age, male gender, higher nonplanning scores and HCV infection were independent factors for the occurrence of risk behaviors. Both groups presented high rates of other sexually transmitted diseases and a low rate of condom use in sexual relations. ConclusionsThis study confirms the higher rate of risk behaviors and the levels of impulsiveness commonly observed in patients with HCV, along with comparisons to patients with HTLV-1.

The relationship between atopy and neurological manifestations in HTLV-1 infection.

Human T-cell lymphotropic virus type 1 (HTLV-1)induces exaggerated Th1 responses, whereas atopy is associated with exacerbated Th2 responses. 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. 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. Abnormal Th1 and Th2 responses coexist in HTLV-1-infected individuals and allergic diseases may worsen the clinical course of HTLV-1 infections.

A Unique T-Cell Receptor Amino Acid Sequence Selected by Human T-Cell Lymphotropic Virus Type 1 Tax 301-309 -Specific Cytotoxic T Cells in HLA-A24:02-Positive Asymptomatic Carriers and Adult T-Cell Leukemia/Lymphoma Patients

We previously reported that the T-cell receptor (TCR) repertoire of human T-cell lymphotropic virus type 1 (HTLV-1) Tax301-309-specific CD8+ cytotoxic T cells (Tax301-309-CTLs) was highly restricted and a particular amino acid sequence motif, the PDR motif, was conserved among HLA-A*24:02-positive (HLA-A*24:02+) adult T-cell leukemia/lymphoma (ATL) patients who had undergone allogeneic hematopoietic cell transplantation (allo-HSCT). Furthermore, we found that donor-derived PDR+ CTLs selectively expanded in ATL long-term HSCT survivors with strong CTL activity against HTLV-1. On the other hand, the TCR repertoires in Tax301-309-CTLs of asymptomatic HTLV-1 carriers (ACs) remain unclear. In this study, we directly identified the DNA sequence of complementarity-determining region 3 (CDR3) of the TCR-β chain of Tax301-309-CTLs at the single-cell level and compared not only the TCR repertoires but also the frequencies and phenotypes of Tax301-309-CTLs between ACs and ATL patients. We did not observe any essential difference in the frequencies of Tax301-309-CTLs between ACs and ATL patients. In the single-cell TCR repertoire analysis of Tax301-309-CTLs, 1,458 Tax301-309-CTLs and 140 clones were identified in this cohort. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-β CDR3, was exclusively observed in all ACs and ATL patients. However, there was no correlation between PDR+ CTL frequencies and HTLV-1 proviral load (PVL). In conclusion, we have identified, for the first time, a unique amino acid sequence, PDR, as a public TCR-CDR3 motif against Tax in HLA-A*24:02+ HTLV-1-infected individuals. Further investigations are warranted to elucidate the role of the PDR+ CTL response in the progression from carrier state to ATL.IMPORTANCE ATL is an aggressive T-cell malignancy caused by HTLV-1 infection. The HTLV-1 regulatory protein Tax aggressively promotes the proliferation of HTLV-1-infected lymphocytes and is also a major target antigen for CD8+ CTLs. In our previous evaluation of Tax301-309-CTLs, we found that a unique amino acid sequence motif, PDR, in CDR3 of the TCR-β chain of Tax301-309-CTLs was conserved among ATL patients after allo-HSCT. Furthermore, the PDR+ Tax301-309-CTL clones selectively expanded and showed strong cytotoxic activities against HTLV-1. On the other hand, it remains unclear how Tax301-309-CTL repertoire exists in ACs. In this study, we comprehensively compared Tax-specific TCR repertoires at the single-cell level between ACs and ATL patients. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-β CDR3, was conserved in all ACs and ATL patients, regardless of clinical subtype in HTLV-1 infection.

Risk Factors for Erectile Dysfunction in Men With HTLV-1

BackgroundErectile dysfunction (ED) occurs in more than 50% of patients with human T-cell lymphotropic virus type 1 (HTLV-1) infection. In the general population, atherosclerosis is the main risk factor related to ED. AimTo compare the contribution of neurologic disorders from HTLV-1 with that of atherosclerosis as risk factors for ED in men with HTLV-1. MethodsIn this cross-sectional study, men 18 to 70 years old with HTLV-1 were classified into one of two groups according to the presence or absence of ED. They were compared for obesity, waist circumference, dyslipidemia, metabolic syndrome, diabetes mellitus, high blood pressure, and neurologic manifestations. Comparisons between proportions were performed using the χ2 or Fisher exact test. Logistic regression analysis was performed to identify predictors of ED. Subjects with HTLV-1 were classified into three groups based on Osame's Disability Motor Scale and the Expanded Disability Status Scale: (i) HTLV-1 carriers; (ii) probable HTLV-1–associated myelopathy or tropical spastic paraparesis; and (iii) definitive HTLV-1–associated myelopathy or tropical spastic paraparesis. The International Index of Erectile Function was used to determine the degree of ED. ResultsIn univariate logistic regression, age older 60 years (P = .003), diabetes mellitus (P = .042), and neurologic disease (P < .001) were associated with ED. In the multivariate model, the odds of ED was highest in patients with neurologic disease (odds ratio = 22.1, 95% CI = 5.3–92.3), followed by high blood pressure (odds ratio = 6.3, 95% CI = 1.4-30.5) and age older than 60 years (odds ratio = 4.6, 95% CI = 1.3–17.3). Clinical ImplicationsIn men infected with HTLV-1, neurologic dysfunction is a stronger predictor of ED than risk factors for atherosclerosis. Strengths and LimitationsThe small number of patients limited the power of the statistical analysis, but clearly neurologic manifestations had a greater association with ED than risk factors for atherosclerosis, and there was no association between metabolic syndrome and severity of ED. ConclusionNeurologic impairment is the major cause of ED in individuals infected with HTLV-1 and risk factors for atherosclerosis did not have a strong relation with ED in this population.de Oliveira CJV, Neto JAC, Andrade RCP, et al. Risk Factors for Erectile Dysfunction in Men With HTLV-1. J Sex Med 2017;14:1195–1200.

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.

Cognitive impairment is frequent among symptomatic carriers of human T-cell lymphotropic virus type 1 (HTLV-1), regardless of their clinical status

The main goal of this study was to investigate the presence of cognitive impairment in patients infected with HTLV-1 presenting or not TSP/HAM. MethodsCross-sectional study including 104 participants: 37 asymptomatic HTLV-1 carriers, 37 patients diagnosed with TSP/HAM and 30 HTLV-1 negative control patients. Within the HTLV-1 positive group, 53 were female and 21 were male, the average age was 46 (SD=13.5) and the average schooling time was 7.7years (SD=3.3).The sociodemographic variables (genre, age and education) were compared between the three groups. The assessment tools used were: Beck Depression Inventory, Lawton's Activities of Daily Life Scale and a complete neuropsychological battery. The application of these assessment tools was carried out in blind. Both HTLV-1 asymptomatic subjects and HAM/TSP patients showed a lower performance on neuropsychological tests and higher depression scores when compared to the control group. HTLV-1 patients performed poorly in several cognitive domains, but only fluid intelligence, estimated intellectual functioning, immediate and delayed recall of visual memory and information processing speed (in the specific case of patients with TSP/HAM) reached statistical significance when compared with controls. Depression was not associated with cognitive impairment. HTLV-1 carriers presented a higher frequency of cognitive impairment than normal controls.

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.

Neurological disorders of HTLV-1 carriers patients taken care of on the clinic of neurology of the FBDC HTLV center

In this study they described the neurological disorders of 116 carrying patients of the Human T Cell Lymphotropic Virus type 1 (HTLV-1) taken care of in the Clinic of Neurology of the FBDC HTLV Center, from the following question: which were the disorders and neurological states found in the patients of the Clinic of Neurology of the FBDC HTLV Center between September of 2005 and August of 2006? To reach this purpose was carried through, using medical record analysis (documentary analysis) and the neurological examination.

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.

Immunological and viral features in patients with overactive bladder associated with human T‐cell lymphotropic virus type 1 infection

The majority of patients infected with human T-cell lymphotropic virus-type 1 (HTLV-1) are considered carriers, but a high frequency of urinary symptoms of overactive bladder, common in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) have been documented in these patients. The aim of this study was to determine if immunological and viral factors that are seen in HAM/TSP are also observed in these patients. Participants were classified as HTLV-1 carriers (n = 45), HTLV-1 patients suffering from overactive bladder (n = 45) and HAM/TSP (n = 45). Cells from HTLV-1 overactive bladder patients produced spontaneously more proinflammatory cytokines than carriers. TNF-α and IL-17 levels were similar in HAM/TSP and HTLV-1 overactive bladder patients. High proviral load was found in patients with overactive bladder and HAM/TSP and correlated with proinflammatory cytokines. In contrast with findings in patients with HAM/TSP, serum levels of Th1 chemokines were similar in HTLV-1 overactive bladder and carriers. Exogenous addition of regulatory cytokines decreased spontaneous IFN-γ production in cell cultures from HTLV-1 overactive bladder patients. The results show that HTLV-1 overactive bladder and HAM/TSP patients have in common some immunological features as well as similar proviral load profile. The data show that HTLV-1 overactive bladder patients are still able to down regulate their inflammatory immune response. In addition, these patients express levels of chemokines similar to carriers, which may explain why they have yet to develop the same degree of spinal cord damage as seen in patients with HAM/TSP. These patients present symptoms of overactive bladder, which may be an early sign of HAM/TSP.

Renal Transplantation in Patients With Human T-Cell Lymphotropic Virus Type 1

BackgroundRenal transplantation (RTx) in carriers of human T-cell lymphotropic virus type 1 (HTLV-1) has a risk of developing overt leukemia upon immunosuppression. Although there have been a few reports of such cases, it is unclear HTLV-1 carrier if patients on the modern immunosuppressants would develop HTLV-1-associated myelopathy or adult T-cell leukemia lymphoma. MethodsWe retrospectively reviewed the clinical outcomes of RTx in nine HTLV-1 carriers to assess a risk of developing leukemia from 2002 to 2011 using immunosuppression with a calcineurin inhibitor, mycophenolate mofetil (MMF), and steroid. The anti-CD25 monoclonal antibody basiliximab was used for induction. In two cases of ABO-incompatible RTx, the rituximab was also administered before RTx. ResultsThe ratio of male to female subjects was 2 to 7 with an overall mean recipient age of 54.3 ± 8.1 years. We prescribed cyclosporine (n = 5) or tacrolimus (n = 4). There was only one graft loss due to the death caused by aspiration pneumonia with a functioning graft. No one developed overt leukemia with combined treatment with MMF, basiliximab and rituximab. ConclusionWe concluded that RTx in HTLV-1 carriers could be performed using a modern immunosuppressive regimen, without the risk of developing leukemia.

Resistant and disseminated Strongyloides stercoralis infection in a young patient with adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell malignancy associated to the human T-cell lymphotropic virus type 1 (HTLV-1). There are between 10 and 20 million HTLV-1 carriers worldwide, particularly in Southwest Japan, the Caribbean, Central Africa, South America and Papua New-Guinea.