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Among the human T-lymphotropic virus (HTLV) types, HTLV-1 is the most prevalent, and it has been linked to a spectrum of diseases, including HAM/TSP, ATLL, and hyperinfection syndrome or disseminated strongyloidiasis. There is currently no globally standard first-line treatment for HTLV-1 infection and its related diseases. To address this, a comprehensive review was conducted, analyzing 30 recent papers from databases PubMed, CAPES journals, and the Virtual Health Library (VHL). The studies encompassed a wide range of therapeutic approaches, including antiretrovirals, immunomodulators, antineoplastics, amino acids, antiparasitics, and even natural products and plant extracts. Notably, the category with the highest number of articles was related to drugs for the treatment of ATLL. Studies employing mogamulizumab as a new perspective for ATLL received greater attention in the last 5 years, demonstrating efficacy, safe use in the elderly, significant antitumor activity, and increased survival time for refractory patients. Concerning HAM/TSP, despite corticosteroid being recommended, a more randomized clinical trial is needed to support treatment other than corticoids. The study also included a comprehensive review of the drugs used to treat disseminated strongyloidiasis in co-infection with HTLV-1, including their administration form, in order to emphasize gaps and facilitate the development of other studies aiming at better-directed methodologies. Additionally, docking molecules and computer simulations show promise in identifying novel therapeutic targets and repurposing existing drugs. These advances are crucial in developing more effective and targeted treatments against HTLV-1 and its related diseases.
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Human T-lymphotropic virus 1 (HTLV-1) infected individuals remain as asymptomatic carriers (ACs) or can develop the chronic neurological disorder HTLV-1-associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP) or the adult T-cell leukemia/lymphoma (ATLL), and the immunological mechanisms involved in this pathologies need to be elucidated. Recently, it has been demonstrated that induced or naturally developed IgG repertoires obtained from different groups of donors, grouped by immune status, can modulate human T and B cell functions. Here we aimed to evaluate if the IgG obtained from HTLV-1-infected ACs, HAM/TSP, and ATLL patients can differentially modulate the production of cytokines by human T and B cells. With this purpose, we cultured PBMCs with IgG purified from ACs, HAM/TSP, or ATLL donors and evaluated the frequency and intracellular cytokine production by flow cytometry. Our results indicate that IgG from HAM/TSP patients could induce an augment of IL-17-producing CD4+ T cells, reduce the frequency of IL-4-producing CD4+ T cells, increase IFN-γ-producing CD8+ T cells, and reduce IL-4-producing CD8+ T cells. IgG from ATLL could reduce the frequency of IL-4-producing CD4+ T cells, similarly to IgG from HAM/TSP /TSP, and could reduce the frequency of IFN-γ-producing γδT cells without influence on IL-17- and IL4-producing γδT and could reduce the frequency of IL-10- producing B cells. Finally, IgG from both HAM/TSP and ATLL patients could reduce the frequency of IFN-γ producing B cells. In conclusion, these results suggest that these preparations are active, partly overlapping in their effects, and able to elicit distinct effects on target populations.
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Small RNAs (sRNAs) are epigenetic regulators of essential biological processes associated with the development and progression of leukemias, including adult T-cell leukemia/lymphoma (ATLL) caused by human T-cell lymphotropic virus type 1 (HTLV-1), an oncogenic human retrovirus originally discovered in a patient with adult T-cell leukemia/lymphoma. Here, we describe the sRNA profile of a 30-year-old woman with ATLL at the time of diagnosis and after maintenance therapy with the aim of correlating expression levels with response to therapy.
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Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto , Linfoma , Adulto , Feminino , Humanos , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/patologia , Vírus Linfotrópico T Tipo 1 Humano/genética , RNA , Linfoma/complicaçõesRESUMO
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.
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Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Leucemia-Linfoma de Células T do Adulto/imunologia , Leucemia-Linfoma de Células T do Adulto/patologia , Leucemia-Linfoma de Células T do Adulto/virologia , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Infecção Persistente/imunologia , Infecção Persistente/virologiaRESUMO
BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of HTLV associated myelopathy/ Tropical Spastic Paraparesis (HAM/TSP) and Adult T cell leukemia/lymphoma (ATLL), in around 2-5% of the infected individuals. Host genetic background might play a role in disease progression. Several previous studies across many countries report HLA haplotype to be one such factor. Here, we sequenced HLA-A, -B and -C of 66 individuals by Sequence-Based Typing (SBT), and compared the frequency of different alleles among ATLL patients, HAM/TSP patients, asymptomatic carriers and non-infected individuals living in Argentina. RESULTS: The frequency of HLA-A, -B and -C alleles largely matched that of the general population in Argentina. We identified HLA-A*02, HLA-B*35 and HLA-C*07 as associated to protection from ATLL (p = 0.031), susceptibility to HAM/TSP (p < 0.001) and susceptibility to ATLL (p = 0.017), respectively. We also found a strong correlation between high proviral load (PVL) and disease (p = 0.008), but were unable to identify any particular allele associated with high or low PVL. CONCLUSIONS: We have found HLA-A*02, HLA-B*35 and HLA-C*07 to be associated to protection from ATLL (HLA-A*02) and susceptibility to HAM/TSP (HLA-B*35) or to ATLL (HLA-C*07), respectively. Whereas HLA-A*02 protection from ATLL has already been extensively described in other regions of the world, this is the first report that links HLA-B*35 and an increased susceptibility to HAM/TSP. As for HLA-C*07 it has previously been associated to susceptibility to HAM/TSP in other countries but in our population it has been linked to ATLL.
Assuntos
Predisposição Genética para Doença/genética , Antígeno HLA-B35/genética , Infecções por HTLV-I/genética , Paraparesia Espástica Tropical/genética , Adolescente , Adulto , Alelos , Argentina , Progressão da Doença , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Antígeno HLA-A2/genética , Antígenos HLA-C/genética , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/virologia , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica Tropical/virologia , Provírus/genética , Carga Viral , Adulto JovemRESUMO
La leucemia / linfoma de células T en adultos (LLTA) es una enfermedad agresiva de células T maduras activadas causada por el virus linfotrópico de células T humano tipo 1 (HTLV-1). ATL tiene un mal pronóstico debido a la quimiorresistencia intrínseca y la inmunosupresión severa. Las formas agresivas de LLTA, aguda y linfoma, se tratan con quimioterapia asociada con agentes antirretrovirales (AZT / IFN). Sin embargo, no han logrado un impacto en la supervivencia, que oscila entre 8 y 10 meses, respectivamente. Los pacientes con formas de LLTA crónicas y latentes tienen un mejor pronóstico, pero la supervivencia a largo plazo también es deficiente, tanto cuando estos pacientes se manejan con una política de espera vigilante o con quimioterapia. Aparentemente, las costuras AZT / IFN benefician a estos pacientes. Mientras tanto, la prevención de la diseminación del HTLV-1 es imprescindible en las políticas de salud pública, tanto por tamizaje del virus en bancos de sangre como a mujeres embarazadas para reducir / evitar la transmisión vertical del virus.
Adult T-cell leukemia/lymphoma (ATL) is an aggressive disease of mature activated T cell caused by human T-cell lymphotropic virus type 1 (HTLV-1). ATL carries a bad prognosis due to intrinsic chemoresistance and severe immunosuppression. The aggressive ATL forms, acute and lymphoma, are treated with chemotherapy associated with antiretroviral agents (AZT/IFN) the acute form. However, they have failed to achieve an impact on survival, that ranges from 8-10 months, respectively. Patients with chronic and smoldering ATL forms, have a better prognosis, but long term survival is poor as well, when these patients are managed with a watchfulwaiting policy or with chemotherapy. Apparently, AZT/IFN seams to benefit these patients. Meanwhile, prevention of dissemination of HTLV-1, is a must in public health policies, performing screening in blood banks and a screening to pregnant women to reduce/avoid vertical transmission of the virus.
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This narrative review, which is based on a systematic literature search following the PRISMA guidelines, provides a general overview of Human T-cell Lymphotropic Virus type 1 (HTLV-1) and associated diseases: Adult T-cell Leukaemia-Lymphoma (ATLL) and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in Latin America, focusing on epidemiology and prevention. Using the published information on HTLV-1, ATLL and HAM/TSP prevalence, we present comprehensive and accurate maps and tables, and developed an algorithm to assist in the prevention of HTLV-1 transmission through breastfeeding while considering socio-economic status. Latin America is an interesting scenario to study HTLV-1 because of the diverse origin of its population. Apart from the expected high prevalence in inhabitants of African ancestry, the presence of endemic foci affecting indigenous populations is particularly striking. ATLL prevention is the biggest challenge in this field. Most ATLL cases are transmitted through breastfeeding; thus, prevention methods to avoid ATLL in endemic countries have to be focused on this. In view of the high inequality in most Latin American countries, reduction in breastfeeding duration, freezing/thawing and pasteurisation of breastmilk can be suitable interventions in poor settings, considering that avoiding the risk of malnutrition and infant mortality must be the priority.
Cette revue narrative, qui repose sur une recherche bibliographique systématique conforme aux recommandations de PRISMA, fournit un aperçu général sur le virus lymphotropique des lymphocytes T humaines de type 1 (HTLV-1) et les maladies associées: Le lymphome leucémique des cellules T d'adulte (ATLL)) et la myélopathie/paraparésie spastique tropicale (HAM/TSP) associée à HTLV-1 en Amérique latine, en se focalisant sur l'épidémiologie et la prévention. En utilisant les informations publiées sur la prévalence de HTLV-1, ATLL et HAM/TSP, nous présentons des cartes et des tableaux complets et précis et avons développé un algorithme pour aider à la prévention de la transmission du HTLV-1 par l'allaitement tout en tenant compte du statut socioéconomique. L'Amérique latine est un scénario intéressant pour l'étude de HTLV-1 en raison de la diversité des origines de sa population. Outre la forte prévalence escomptée chez les habitants de descendance africaine, la présence de foyers endémiques affectant les populations autochtones est particulièrement frappante. La prévention de l'ATLL est le plus gros défi dans ce domaine. La plupart des cas d'ATLL sont transmis par l'allaitement. Ainsi, les méthodes de prévention pour éviter l'ATLL dans les pays d'endémie doivent être concentrées sur cela. Compte tenu de la forte inégalité qui règne dans la plupart des pays d'Amérique latine, la réduction de la durée de l'allaitement, la congélation/décongélation et la pasteurisation du lait maternel peuvent constituer des interventions appropriées dans les milieux pauvres, tout en considérant que la priorité est d'éviter les risques de malnutrition et de mortalité infantile.
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Infecções por HTLV-I/epidemiologia , Infecções por HTLV-I/prevenção & controle , Humanos , América Latina/epidemiologiaRESUMO
To gain insight into the origin, evolution, dissemination and viral factors affecting HTLV-1-associated diseases, knowing the complete viral genome sequences is important. So far, no full-length HTLV-1 genome sequence has been reported from Iran. Here we report the complete nucleotide sequence of HTLV-1 viruses isolated from adult T cell leukemia/lymphoma (ATLL) patients from this region. The genome size of HTLV-1-MhD (Mashhad) was found to be 9036â¯bp and sequence analysis of the LTR region showed that it belongs to cosmopolitan subtype A. Comparing the sequences with isolates from another endemic area (HTLV-1ATK) revealed variations in the U3 region (~3.4%), while there was 99.1% and 97.0% similarity in R and U5 regions, respectively. The nucleotide sequences of HTLV-1 gag, pro and pol genes had a difference of 1.1% compared with HTLV-1 ATK with 16 nucleotides replaced in the gag and 27 in the pol regions. There was no variability in the amino acid sequences in the p24gag, however three residues were different in the p19gag and one in the p15gag. The nucleotide sequence of env showed a divergence of 1.5% compared to ATK with 22-nucleotide variation. The HTLV-1-MhD Tax, p13, p30, and p12 had 99.1, 100, 98.8, and 98%, respectively similarity with the prototype strain. Four amino acid changes were detected in ORF1 and ORF2 products p12 and p30, respectively, while the p13 region showed 100% conservation. The nucleotide identity between the isolates of Mashhad and those isolated from France, Germany, China, Canada and Brazil was 99.1%, 99.2%, 97.9%, 99% and 99.3%, respectively. Four amino acid changes compared with HTLV-1ATK from Japan were detected in ORF1 and ORF2 products p12 and p30, respectively, while the p13 region showed 100% conservation. This data could provide information regarding the evolutionary history, phylogeny, origin of the virus and vaccine design.
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Vírus Linfotrópico T Tipo 1 Humano/genética , Leucemia-Linfoma de Células T do Adulto/virologia , Fases de Leitura Aberta/genética , Peptídeo Hidrolases/genética , Fatores de Transcrição/genética , Proteínas Virais Reguladoras e Acessórias/genética , Sequência de Aminoácidos , Sequência de Bases , Brasil , Canadá , China , DNA Viral/genética , Feminino , França , Genes Virais/genética , Alemanha , Humanos , Irã (Geográfico) , Japão , Masculino , Pessoa de Meia-Idade , Sequências Repetitivas de Ácido Nucleico/genéticaRESUMO
Resumen La leucemia/linfoma T del adulto (LLTA) de tipo linfomatoso es un subtipo del linfoma de las células T, causado por la infección del virus linfotrópico de células T humanas tipo 1 (HTLV-1); el cual genera una integración proviral en el ADN del hospedero y expansión clonal de linfocitos T. Presentamos el caso de una mujer de 20 años que desarrolló linfadenopatías múltiples, hepatoesplenomegalia y fiebre, con serología positiva para HTLV-1 y reacción de polimerasa en cadena (RPC) con la integración proviral en el ADN del hospedero. La inmunohistoquímica en un ganglio linfático fue positiva para células T CD4+ y CD8+. La LLTA ha sido descrito en todas las áreas endémicas del HTLV-1; sin embargo, existen diferencias en la edad de presentación según la región: 40 a 50 años en América del Sur y 60 años en Japón. Presentamos uno de los pocos casos reportados de LLTA de tipo linfomatoso en adultos jóvenes.
Adult T cell lymphocyte leukemia/lymphoma (ATLL) is a subtype of T-cell lymphoma caused by infection of the human T-cell lymphotropic virus type 1 (HTLV-1); which generates a pro-viral integration into the host DNA, resulting in a clonal expansion of T lymphocytes. We present the case of a 20-year-old woman who developed multiple lymphadenopathies, hepatosplenomegaly and fever, serum positivity for HTLV-1 and proviral integration in the host DNA, demonstrated by polymerase chain reaction (PCR). Immunohistochemistry of lymphoid node was positive to CD4+ and CD8+ T cells. ATLL has been described in all HTLV-1 endemic areas, however, there are differences in the mean age of its presentation in such areas: 40 to 50 years in South America, 60 years in Japan. We showed one of few reported cases of the lymphoma type of ATLL in young adults.
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Humanos , Feminino , Adulto Jovem , Vírus Linfotrópico T Tipo 1 Humano , Infecções por HTLV-I/virologia , Leucemia-Linfoma de Células T do Adulto/virologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Ensaio de Imunoadsorção Enzimática , Evolução Fatal , Linfadenopatia/virologiaRESUMO
Human T lymphotropic virus type 1 (HTLV-1) is the etiological agent of HTLV-1-associated myelopathy, and adult T cell lymphoma/leukemia (ATL/L). Pulmonary complications such as alveolitis and bronchiectasis were found in individuals who develop TSP/HAM due to chronic inflammation. These individuals showed image anomalies in CT scans and changes in pulmonary function parameters distinctive of pulmonary disease. Furthermore, infected individuals have a greater susceptibility to pulmonary tuberculosis either due to changes in the innate immune response, in asymptomatic carriers, or to an opportunistic disease linked to immunodepression, in individuals who develop ATL/L. This summary addresses the general lack of knowledge regarding the relationship between HTLV-1 and pulmonary diseases and provides direction for future work.
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Human T-lymphotropic viruses (HTLV) are Deltaretroviruses that infect millions of individuals worldwide via the same transmission routes as HIV. With the aim of exposing the possible re-emergence of HTLV in West Africa since discovery, a systematic review was carried out, focusing on the distribution of the virus types and significance of frequent indeterminate reports, while highlighting the need for mandatory routine blood screening. Capturing relevant data from discovery till date, sources searched were Google Scholar, CrossRef, NCBI (PubMed), MEDLINE, Research Gate, Mendeley, abstracts of Conferences and Proceedings, organization websites and reference lists of selected papers. A total of 2626 references were initially retrieved using search terms: Worldwide prevalence of HTLV, HTLV in Africa, HTLV in West Africa, HTLV subtypes, HTLV 3 and 4 in Africa, HTLV of African origin, HTLV seroindeterminate results, Spread of HTLV. These references were rigorously trimmed down to 76. Although evidence shows that HTLV is still endemic in the region, West Africa lacks recent epidemiological prevalence data. Thorough investigations are needed to ascertain the true cause of indeterminate Western Blot results. It is imperative that routine screening for HTLVs be mandated in West African health care facilities.
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Infecções por Deltaretrovirus/epidemiologia , Deltaretrovirus , África Ocidental/epidemiologia , Infecções por Deltaretrovirus/transmissão , Feminino , Humanos , Masculino , Prevalência , Fatores de Risco , Estudos SoroepidemiológicosRESUMO
Forkhead box P3 (FOXP3) is a specific marker for regulatory T-cells (Tregs). We report 6 cases of T-cell lymphomas with Treg phenotype based on diffuse positivity for FOXP3 in tumor cells. The patients showed a median age of 56â¯years with a male predominance. Sites of disease included lymph nodes (4), skin (2), subcutaneous tissue (1) and bone marrow (1). All cases showed monomorphic large cells, some with Hodgkin-like or anaplastic cells. All cases expressed pan T-cell markers and lacked cytotoxic markers; one case showed diffuse PD1 staining. Only one case harbored human T-lymphotrophic virus (HTLV)-1 DNA within tumor cells and was classified as adult T-cell leukemia/lymphoma (ATLL). Among 5 HTLV1-negative cases, 3 were classified as peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) and 2 fulfilled criteria for ALK-negative anaplastic large cell lymphoma (ALCL) with diffuse and strong CD30 positivity. We concluded that Treg phenotype may be rarely seen in HTLV1-negative cases, such as PTCL, NOS and ALK-negative ALCL. Our findings expand the spectrum of T-cell lymphomas with regulatory phenotype and suggest that consideration should be given to HTLV1 DNA testing in the appropriate clinical setting to rule out ATLL.
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Quinase do Linfoma Anaplásico/imunologia , Fatores de Transcrição Forkhead/imunologia , Linfoma Anaplásico de Células Grandes/genética , Linfoma de Células T/patologia , Adulto , Idoso , Biomarcadores/análise , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Linfoma Anaplásico de Células Grandes/imunologia , Linfoma Anaplásico de Células Grandes/patologia , Linfoma de Células T/imunologia , Linfoma de Células T Periférico/imunologia , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Receptores Proteína Tirosina Quinases/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologiaRESUMO
ABSTRACT Human T-lymphotropic viruses (HTLV) are Deltaretroviruses that infect millions of individuals worldwide via the same transmission routes as HIV. With the aim of exposing the possible re-emergence of HTLV in West Africa since discovery, a systematic review was carried out, focusing on the distribution of the virus types and significance of frequent indeterminate reports, while highlighting the need for mandatory routine blood screening. Capturing relevant data from discovery till date, sources searched were Google Scholar, CrossRef, NCBI (PubMed), MEDLINE, Research Gate, Mendeley, abstracts of Conferences and Proceedings, organization websites and reference lists of selected papers. A total of 2626 references were initially retrieved using search terms: Worldwide prevalence of HTLV, HTLV in Africa, HTLV in West Africa, HTLV subtypes, HTLV 3 and 4 in Africa, HTLV of African origin, HTLV seroindeterminate results, Spread of HTLV. These references were rigorously trimmed down to 76. Although evidence shows that HTLV is still endemic in the region, West Africa lacks recent epidemiological prevalence data. Thorough investigations are needed to ascertain the true cause of indeterminate Western Blot results. It is imperative that routine screening for HTLVs be mandated in West African health care facilities.
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Humanos , Masculino , Feminino , Infecções por Deltaretrovirus/epidemiologia , Deltaretrovirus , Infecções por Deltaretrovirus/transmissão , Estudos Soroepidemiológicos , Prevalência , Fatores de Risco , África Ocidental/epidemiologiaRESUMO
Abstract Hodgkin-like ATLL is a rare variant of adult T-cell leukemia/lymphoma (ATLL), a disease caused by human T-cell lymphotropic virus type-1 (HTLV-1). At admission, a 46-year-old female presented with lymphadenomegaly, lymphocytosis, slight elevation of LDH blood level, and acid-alcohol resistant bacilli in sputum and was being treated for pulmonary tuberculosis (Tb). She had lymphocytosis in the previous 20 months. Serology for HTLV-1 was positive. Lymph node was infiltrated by medium-sized lymphocytes with scattered Hodgkin and Reed-Sternberg-like cells CD30+, CS1-4+, and CD79a+. Background cells were CD4+ and CD25+. A clinical diagnosis of favorable chronic ATLL was given. She was treated with chemotherapy but later progressed to acute ATLL and ultimately died. Hodgkin-like ATLL should be considered in the histological differential diagnosis with Hodgkin lymphoma since treatment and prognosis of these diseases are distinct. It is also important to search for HTLV-1 infection in patients with unexplained prolonged lymphocytosis.
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Humanos , Feminino , Pessoa de Meia-Idade , Doença de Hodgkin/patologia , Infecções por HTLV-I/patologia , Leucemia-Linfoma de Células T do Adulto/patologia , Linfocitose/patologia , Biópsia , Ensaio de Imunoadsorção Enzimática , Doença de Hodgkin/virologia , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Leucemia-Linfoma de Células T do Adulto/virologia , Evolução Fatal , Linfocitose/virologia , Linfonodos/patologiaRESUMO
Hodgkin-like ATLL is a rare variant of adult T-cell leukemia/lymphoma (ATLL), a disease caused by human T-cell lymphotropic virus type-1 (HTLV-1). At admission, a 46-year-old female presented with lymphadenomegaly, lymphocytosis, slight elevation of LDH blood level, and acid-alcohol resistant bacilli in sputum and was being treated for pulmonary tuberculosis (Tb). She had lymphocytosis in the previous 20 months. Serology for HTLV-1 was positive. Lymph node was infiltrated by medium-sized lymphocytes with scattered Hodgkin and Reed-Sternberg-like cells CD30+, CS1-4+, and CD79a+. Background cells were CD4+ and CD25+. A clinical diagnosis of favorable chronic ATLL was given. She was treated with chemotherapy but later progressed to acute ATLL and ultimately died. Hodgkin-like ATLL should be considered in the histological differential diagnosis with Hodgkin lymphoma since treatment and prognosis of these diseases are distinct. It is also important to search for HTLV-1 infection in patients with unexplained prolonged lymphocytosis.
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Infecções por HTLV-I/patologia , Doença de Hodgkin/patologia , Leucemia-Linfoma de Células T do Adulto/patologia , Linfocitose/patologia , Biópsia , Ensaio de Imunoadsorção Enzimática , Evolução Fatal , Feminino , Doença de Hodgkin/virologia , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Humanos , Leucemia-Linfoma de Células T do Adulto/virologia , Linfonodos/patologia , Linfocitose/virologia , Pessoa de Meia-IdadeRESUMO
The typical characteristics of mesenchymal stem cells (MSCs) can be affected by inflammatory microenvironment; however, the exact contribution of HTLV-1 to MSC dysfunction remains to be elucidated. In this study, we demonstrated that MSC cell surface molecules VCAM-1 and ICAM-1 are upregulated by contact with HTLV-1, and HLA-DR was most highly expressed in MSCs co-cultured with MT2 cells. The expression levels of VCAM-1 and HLA-DR were increased in MSCs cultured in the presence of PBMCs isolated from HTLV-1-infected symptomatic individuals compared with those cultured with cells from asymptomatic infected individuals or healthy subjects. HTLV-1 does not impair the MSC differentiation process into osteocytes and adipocytes. In addition, MSCs were efficiently infected with HTLV-1 in vitro through direct contact with HTLV-1-infected cells; however, cell-free virus particles were not capable of causing infection. In summary, HTLV-1 can alter MSC function, and this mechanism may contribute to the pathogenesis of this viral infection.
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Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Células-Tronco Mesenquimais/virologia , Diferenciação Celular , Células Cultivadas , Infecções por HTLV-I/genética , Infecções por HTLV-I/imunologia , Infecções por HTLV-I/fisiopatologia , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Fenótipo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/imunologiaRESUMO
BACKGROUND: Human T cell lymphotropic virus type 1 (HTLV-1) infection has been associated with recurrent and disseminated strongyloidiasis and adult T cell leukemia/lymphoma (ATLL). METHODS: We compared immunological aspects and markers for ATLL in HTLV-1 patients with or without strongyloidiasis, and evaluated the influence of Strongyloides stercoralis treatment on the immune response and clinical outcomes of HTLV-1 infection. RESULTS: Levels of TNFα and IFNγ were lower in patients coinfected with HTLV-1 and S. stercoralis than in patients with HTLV-1 only (p < 0.05), and there was an increase in TNFα levels after anthelmintic treatment. Levels of sIL-2R were higher in patients with HTLV-1 coinfected with S. stercoralis and anthelmintic treatment decreased sIL-2R levels (p < 0.05). The one patient who developed ATLL was coinfected with S. stercoralis. CONCLUSION: These data show that helminthic infection has a modulatory role in HTLV-1 infection and that S. stercoralis may be a cofactor in the development of ATLL.
Assuntos
Anti-Helmínticos/uso terapêutico , Infecções por HTLV-I/tratamento farmacológico , Receptores de Interleucina-2/sangue , Estrongiloidíase/tratamento farmacológico , Fator de Necrose Tumoral alfa/sangue , Adulto , Animais , Coinfecção , Progressão da Doença , Feminino , Infecções por HTLV-I/sangue , Infecções por HTLV-I/complicações , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Humanos , Leucemia-Linfoma de Células T do Adulto/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-2/imunologia , Strongyloides stercoralis/imunologia , Estrongiloidíase/sangue , Estrongiloidíase/complicações , Estrongiloidíase/imunologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologiaRESUMO
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.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Portador Sadio/imunologia , Glutationa/metabolismo , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Acetilcisteína/metabolismo , Adulto , Idoso , Linfócitos T CD8-Positivos/virologia , Proliferação de Células , Células Cultivadas , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Espaço Intracelular/metabolismo , Ativação Linfocitária , Masculino , Metionina Sulfoximina/análogos & derivados , Metionina Sulfoximina/metabolismo , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Adulto JovemRESUMO
BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is a distinctive peripheral T- lymphocytic malignancy associated with human T-cell lymphotropic virus type 1 (HTLV-1). It may closely resemble other skin lymphomas, particularly mycosis fungoides (MF). CASE REPORT: A 38-year-old woman presented some ellipsoid scaling patches lasting 18 months and developed a large tumoral lesion in the abdomen, which were previously diagnosed as MF. Although histopathologic and immunohistochemistry findings were in consonance with this diagnosis, the fast progression of the disease raised the suspicion that it could represent another type of T-cell lymphoma. The work-up revealed a positive anti-HTLV-1 serology and molecular studies confirmed the monoclonal integration of HTLV-1 provirus into neoplastic cells of the skin, but not into circulating lymphocytes. Extensive investigations were unable to demonstrate any systemic involvement. The final diagnosis was of primary cutaneous type of ATLL. The patient was submitted to a chemotherapy regimen with cyclophosphamide, doxorubicin, vincristine and prednisone, later to conjugated dexamethasone and surgical cytoreduction and then to a second line treatment with gemcitabine, resulting in partial response. A bone marrow heterologous transplantation was performed, but failed to achieve a sustained remission. DISCUSSION: ATLL is a rare lymphoid malignancy in non-endemic HTLV-1 areas, the diagnosis of which could be missed if not highly suspected. In addition to the four subtypes of Shimoyama classification (acute, lymphomatous, chronic and smoldering), a fifth one denominated primary cutaneous and characterized by presence of lesions only in the skin had been proposed and is herein exemplified.
RESUMO
Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive disease that occurs in individuals infected with the human T lymphotropic virus type 1 (HTLV-1). Patients with aggressive ATLL have a poor prognosis because the leukemic cells are resistant to conventional chemotherapy. We have investigated the therapeutic efficacy of a biphosphinic cyclopalladated complex {Pd(2) [S(-)C(2), N-dmpa](2) (µ-dppe)Cl(2)}, termed C7a, in a patient-derived xenograft model of ATLL, and investigated the mechanism of C7a action in HTLV-1-positive and negative transformed T cell lines in vitro. In vivo survival studies in immunocompromised mice inoculated with human RV-ATL cells and intraperitoneally treated with C7a led to significantly increased survival of the treated mice. We investigated the mechanism of C7a activity in vitro and found that it induced mitochondrial release of cytochrome c, caspase activation, nuclear condensation and DNA degradation. These results suggest that C7a triggers apoptotic cell death in both HTLV-1 infected and uninfected human transformed T-cell lines. Significantly, C7a was not cytotoxic to peripheral blood mononuclear cells (PBMC) from healthy donors and HTLV-1-infected individuals. C7a inhibited more than 60% of the ex vivo spontaneous proliferation of PBMC from HTLV-1-infected individuals. These results support a potential therapeutic role for C7a in both ATLL and HTLV-1-negative T-cell lymphomas.