Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases.

BACKGROUND: Human T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation. METHODS: Here, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples. RESULTS: We found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients' samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation. CONCLUSIONS: These results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current "wait and see approach" in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits.

Human T-cell Lymphotropic Virus Type I Associated with Amyotrophic Lateral Sclerosis Syndrome: Immunopathological Aspects and Treatment Options.

Human T-cell lymphotropic virus type I (HTLV-I) is a retrovirus related to infectious myelopathies, neoplasms, lymphomas, leukemias, and amyotrophic lateral sclerosis (ALS). It is acquired through sexual transmission, transfusion of blood products, and breastfeeding. The increased expression of human endogenous retrovirus K (HERV-K) in the brain tissue of patients with ALS has been demonstrated, a finding that supports the relationship between the virus and this disease. Therapeutic options include supportive measures and symptomatic treatment with anti-inflammatory medications including steroids, cyclosporines, pentoxifylline, danazol, interferons, and vitamin C. New management proposals are being implemented with valproic acid that acts to facilitate the recognition of the virus by the immune system and with zidovudine antivirals focused on reducing viral load. The purpose of this paper is to describe a clinical case that exhibits clinical signs and evidence of motor neuron compromise as described in electrophysiology studies along with positive laboratory tests for the HTLV-I virus.

HTLV-1, the Other Pathogenic Yet Neglected Human Retrovirus: From Transmission to Therapeutic Treatment.

Going back to their discovery in the early 1980s, both the Human T-cell Leukemia virus type-1 (HTLV-1) and the Human Immunodeficiency Virus type-1 (HIV-1) greatly fascinated the virology scene, not only because they were the first human retroviruses discovered, but also because they were associated with fatal diseases in the human population. In almost four decades of scientific research, both viruses have had different fates, HTLV-1 being often upstaged by HIV-1. However, although being very close in terms of genome organization, cellular tropism, and viral replication, HIV-1 and HTLV-1 are not completely commutable in terms of treatment, especially because of the opposite fate of the cells they infect: death versus immortalization, respectively. Nowadays, the antiretroviral therapies developed to treat HIV-1 infected individuals and to limit HIV-1 spread among the human population have a poor or no effect on HTLV-1 infected individuals, and thus, do not prevent the development of HTLV-1-associated diseases, which still lack highly efficient treatments. The present review mainly focuses on the course of HTLV-1 infection, from the initial infection of the host to diseases development and associated treatments, but also investigates HIV-1/HTLV-1 co-infection events and their impact on diseases development.

Retinal Nerve Fiber Layer Thickness in Human T-cell Lymphotropic Virus Type 1 Patients.

PURPOSE: To determine whether there is an optic neuropathy (ON) in patients with human T-cell lymphotropic virus type 1 (HTLV-1) infection. METHODS: We included HTLV-1 asymptomatic carriers (a.c.HTLV-1) and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) patients between January 1st, 2014 and March 31st, 2015. All patients had complete eye examination. The visual acuity (VA) and retinal nerve fiber layer (RNFL) thickness were measured and compared to age- and sex-matched control groups including patients seen in our refraction clinic with no previous medical or surgical history. RESULTS: Thirty-one a.c.HTLV-1 (group 1) and 29 TSP/HAM patients (group 2) were included. The average RNFL thickness was 99.9 ± 14.3 µm in group 1 and 87.8 ± 19.2 µm in group 2. The average RFNL thicknesses were lower in both groups, when compared to controls. The difference was significant in patients with TSP/HAM (87.8 ± 19.2 µm vs. 97 ± 7.8 µm; p = 0.003) who also had significantly decreased VA. CONCLUSIONS: We report here the first study about the RNFL thickness in patients with TSP/HAM. In these patients, there is decrease of the RNFL thickness with subtle but definite decrease of VA. This suggests that subclinical ON occurs in the natural history of the disease. The diagnosis of TSP/HAM must be evoked as a differential of primary progressive multiple sclerosis in a population at risk. Moreover, RNFL thinning with no evidence of glaucoma should raise suspicion for HTLV-1 infection and TSP/HAM in a population at risk.

Seroprevalence of human T-lymphotropic virus antibodies among patients with lymphoid malignancies at a tertiary center in Lagos, Nigeria.

BACKGROUND: There is a significant association of human T-lymphotropic viruses (HTLV) with lymphoid malignancies. HTLV causes a lymphoproliferative malignancy of CD4-activated cells called adult T-cell leukemia/lymphoma (ATL) and a chronic myelopathy called tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). This study aims to determine the prevalence of HTLV among patients with lymphoid malignancies at a tertiary center in Lagos. METHODS: A cross-sectional study was carried out at the hematology clinic of the Lagos State University Teaching Hospital. After obtaining consent, approximately 5 mL of venous blood was collected from each subject. The serum was separated and stored at -20°C. Sera were assayed for HTLV by an enzyme-linked immunoassay (ELISA) for the determination of antibodies to HTLV-1 and -2. Western blot confirmatory testing was done on reactive samples. All patients were also screened for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) by rapid kits. RESULTS: A total of 39 patients with lymphoid malignancies were enrolled, consisting of 24 (61.5%) with solid malignancies, while 15 (38.5%) had leukemia. Only two patients (5.1%) with lymphoid malignancies were reactive on the ELISA test. On confirmatory testing with Western blot, two patients (5.1%) with lymphoid malignancies were also positive for HTLV. All patients were HIV negative, but four were positive to HBsAg and HCV. There was no association between history of previous blood transfusion and positivity to HTLV (P=0.544). CONCLUSION: A prevalence of 5.1% of HTLV among patients with lymphoid malignancies was found in this study, and previous history of blood transfusion was not found to be a significant cause of HTLV infection.

Pain in tropical spastic paraparesis/HTLV-I associated myelopathy patients / Dor em pacientes com paraparesia espástica tropical/mielopatia associada ao HTLV-I

OBJECTIVE: Tropical Spastic Paraparesis/HTLV-I Associated Myelopathy (TSP/HAM) is a chronic myelopathy, and pain has been mentioned as a frequent sensory symptom in this condition. The authors aimed at analyzing this symptom in a TSP/HAM patients series. METHOD: For this, 46 patients were analyzed considering demographic and clinical characteristics and complaint of pain as to verbal description, time of onset and classification, correlated with the degree of motor disability and type of pain. RESULTS: Among the 46 TSP/HAM patients, 28 (60.8 percent) complained of pain, predominant in the early phase of the disease. Most of the patients exhibited neuropathic characteristics of pain, correlated with increased motor disability. CONCLUSION: Pain in TSP/HAM patients is a frequent and early symptom, and the neuropathic type is predominant (57.1 percent) and paralleled with increased incapacitation. The pathogenic involvement of cytokines may possibly be involved in the meaning of this symptom in this condition.

OBJETIVO: A Paraparesia Espástica Tropical/Mielopatia Associada ao HTLV-I (PET/MAH) é uma mielopatia crônica, e a dor tem sido mencionada como um sintoma sensitivo freqüente nessa condição. Os autores objetivam analisar esse sintoma numa série de pacientes com PET/MAH. MÉTODO: Para isso, 46 pacientes foram analisados considerando características demográficas e clínicas, e queixa de dor do ponto de vista da descrição verbal, tempo de início e classificação, correlacionados com o grau de incapacitação motora e o tipo de dor. RESULTADOS: Dentre os 46 pacientes com PET/MAH, 28 (60,8 por cento) se queixavam de dor, predominando na fase inicial da doença. A maioria dos pacientes evidenciou características de dor neuropática, correlacionada com aumento da incapacitação motora. CONCLUSÃO: A dor em pacientes com PET/MAH é um sintoma freqüente e inicial, sendo o tipo neuropático predominante (57,1 por cento) e em paralelo com maior incapacitação. O envolvimento patogênico das citocinas poderá possivelmente estar relacionado com o significado desse sintoma nessa condição clínica.

T CD4+ cells count among patients co-infected with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1): high prevalence of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM)

INTRODUCTION: HIV positive patients co-infected with HTLV-1 may have an increase in their T CD4+ cell counts, thus rendering this parameter useless as an AIDS-defining event. OBJECTIVE: To study the effects induced by the co-infection of HIV-1 and HTLV-1 upon CD4+ cells. MATERIAL AND METHODS: Since 1997, our group has been following a cohort of HTLV-1-infected patients, in order to study the interaction of HTLV-1 with HIV and/or with hepatitis C virus (HCV), as well as HTLV-1-only infected asymptomatic carriers and those with tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). One hundred and fifty HTLV-1-infected subjects have been referred to our clinic at the Institute of Infectious Diseases "Emílio Ribas", São Paulo. Twenty-seven of them were also infected with HIV-1 and HTLV-1-infection using two ELISAs and confirmed and typed by Western Blot (WB) or polymerase chain reaction (PCR). All subjects were evaluated by two neurologists, blinded to the patient's HTLV status, and the TSP/HAM diagnostic was based on the World Health Organization (WHO) classification. AIDS-defining events were in accordance with the Centers for Disease Control (CDC) classification of 1988. The first T CD4+ cells count available before starting anti-retroviral therapy are shown compared to the HIV-1-infected subjects at the moment of AIDS defining event. RESULTS: A total of 27 HIV-1/HTLV-1 co-infected subjects were identified in this cohort; 15 already had AIDS and 12 remained free of AIDS. The median of T CD4+ cell counts was 189 (98-688) cells/mm³ and 89 (53-196) cells/mm³ for co-infected subjects who had an AIDS-defining event, and HIV-only infected individuals, respectively (p = 0.036). Eight of 27 co-infected subjects (30 percent) were diagnosed as having a TSP/HAM simile diagnosis, and three of them had opportunistic infections but high T CD4+ cell counts at the time of their AIDS- defining event. DISCUSSION: Our results indicate that...

INTRODUÇÃO: A possibilidade que a co-infecção pelo vírus da leucemia de células T humana do tipo 1 (HTLV-1) em indivíduos infectados pelo vírus da imunodeficiência humana do tipo 1 poderia falsamente elevar o número de linfócitos T CD4+ no momento do evento definidor de aids, inferindo que essa contagem poderia ser um marcador laboratorial incompleto nos pacientes com a co-infecção HIV-1/HTLV-1. OBJETIVO: Estudar a interação entre o HIV-1 e a co-infecção como o HTLV-1. MATERIAL E MÉTODO: Desde 1997, nosso grupo tem seguido uma coorte de pacientes para estudar a interação entre HIV e/ou vírus da hepatite C (HCV), como também pacientes assintomáticos ou com TSP/HAM. 150 pacientes infectados pelo HTLV-1, encaminhados à clínica de HTLV do Instituto de Infectologia Emilio Ribas, São Paulo, Brasil, foram estudados. Vinte e sete deles estavam co-infectados pelo HIV-1 e HTLV-1, usando dois ELISAs e confirmados tipados pelo WB ou PCR. Todos os pacientes foram avaliados por dois neurologistas, cegos para o status de HTLV e o diagnóstico de TSP/HAM foi baseado na classificação da Organização Mundial de Saúde, 1988. A primeira contagem de células T disponível antes da terapia anti-retroviral foi mostrada para comparar com os pacientes infectados pelo HIV no momento do evento definidor de aids de acordo com Classificação do Centro de controle de Doenças, 1988. RESULTADOS: Um total de 27 HIV-1/HTLV-1 co-infectados foram identificados na coorte, 15 já apresentavam aids e 12 permaneceram sem evento de aids. A mediana de células T CD4 foi de 189 (98-688) células/mm³ e 89 (53-196) células/mm³ nos co-infectados que tinham evento definidor de aids e naqueles com a infecção somente pelo HIV, respectivamente (p = 0,036). Oito dos 27 co-infectados (30 por cento) foram diagnosticados tendo TSP/HAM símile, e três deles mostraram elevada contagem de células T CD4 e apresentaram infecções oportunistas no momento do evento definidor de aids. DISCUSSÃO: Nossos resultados...