RESUMEN
OBJECTIVES: The HTLV-1 infection persists for life, remaining as asymptomatic viral reservoirs in most patients, ensuring the chain of transmission, but around 4% develop adult T-cell leukemia/lymphoma (ATLL). HTLV-1 is an oncogenic retrovirus that transforms CD4+ T lymphocytes and deregulates the lymphoproliferative pathways that contribute to the development of ATLL. To achieve cell transformation, most oncogenic retroviruses use proto-oncogene capture transduction, with proviral integration disrupting the expression of tumor suppressors or proto-oncogenes. THE AIM: We conducted this study on the prevalence of HTLV-1 infection in blood donors to expand the HTLV-1 database, assess the risk of transmission via blood products, as well as evaluate the risk of persistent infection or development of neoplastic diseases in HTLV-1 carriers. MATERIALS AND METHODS: This is a cross-sectional study of blood donors of all categories. For this study, 265 blood donors were recruited at the Centre National de Transfusion Sanguine in Brazzaville. After testing for HTLV-1 antibodies by ELISA, proviral DNA was extracted from all ELISA-positive samples for detection by nested PCR, followed by RT qPCR using specific primers p53 and c-myc for gene expression. RESULTS: 20/265 were positive for anti-HTLV-1 antibody, 5 donors were positive for proviral DNA. The prevalence of HTLV-1 was 1.8%. All HTLV-1-positive donors were male (1.8%), with a positive correlation (p = 0.05); the 1.1% of positive donors were regular, with the majority aged between 31 and 45 years (1.5%), and concubine donors were the most frequent (1.1%). All samples showed normal expression of the p53 and c-myc genes. CONCLUSION: The prevalence, though low, remains a serious problem. No abnormal p53 or c-myc gene expression was detected in HTLV-1-positive donors, which could mean that none of the T lymphocytes in these donors had been transformed by HTLV-1.
Asunto(s)
Donantes de Sangre , Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Proteínas Proto-Oncogénicas c-myc , Proteína p53 Supresora de Tumor , Humanos , Virus Linfotrópico T Tipo 1 Humano/genética , Masculino , Infecciones por HTLV-I/epidemiología , Infecciones por HTLV-I/virología , Infecciones por HTLV-I/genética , Infecciones por HTLV-I/sangre , Adulto , Femenino , Proteína p53 Supresora de Tumor/genética , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-myc/genética , Proto-Oncogenes Mas , Estudios Transversales , Perfilación de la Expresión Génica , Leucemia-Linfoma de Células T del Adulto/virología , Leucemia-Linfoma de Células T del Adulto/epidemiología , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/sangre , Provirus/genética , AdolescenteRESUMEN
Human T-cell leukemia virus type 1 (HTLV-1) infection is linked to the development of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax oncoprotein regulates viral gene expression and persistently activates NF-κB to maintain the viability of HTLV-1-infected T cells. Here, we utilize a kinome-wide shRNA screen to identify the tyrosine kinase KDR as an essential survival factor of HTLV-1-transformed cells. Inhibition of KDR specifically induces apoptosis of Tax expressing HTLV-1-transformed cell lines and CD4 + T cells from HAM/TSP patients. Furthermore, inhibition of KDR triggers the autophagic degradation of Tax resulting in impaired NF-κB activation and diminished viral transmission in co-culture assays. Tax induces the expression of KDR, forms a complex with KDR, and is phosphorylated by KDR. These findings suggest that Tax stability is dependent on KDR activity which could be exploited as a strategy to target Tax in HTLV-1-associated diseases.
Asunto(s)
Supervivencia Celular , Productos del Gen tax , Virus Linfotrópico T Tipo 1 Humano , FN-kappa B , Paraparesia Espástica Tropical , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Productos del Gen tax/metabolismo , Productos del Gen tax/genética , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/fisiología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , FN-kappa B/metabolismo , Paraparesia Espástica Tropical/virología , Paraparesia Espástica Tropical/metabolismo , Apoptosis , Infecciones por HTLV-I/virología , Infecciones por HTLV-I/metabolismo , Linfocitos T CD4-Positivos/virología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T/metabolismo , Linfocitos T/virología , Leucemia-Linfoma de Células T del Adulto/virología , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/patología , Fosforilación , Células HEK293RESUMEN
Adult T-cell leukemia/lymphoma (ATL) occurs after human T-cell leukemia virus type-1 (HTLV-1) infection with a long latency period exceeding several decades. This implies the presence of immune evasion mechanisms for HTLV-1-infected T cells. Although ATL cells have a CD4+CD25+ phenotype similar to that of regulatory T cells (Tregs), they do not always possess the immunosuppressive functions of Tregs. Factors that impart effective immunosuppressive functions to HTLV-1-infected cells may exist. A previous study identified a new CD13+ Treg subpopulation with enhanced immunosuppressive activity. We, herein, describe the paired CD13- (designated as MT-50.1) and CD13+ (MT-50.4) HTLV-1-infected T-cell lines with Treg-like phenotype, derived from the peripheral blood of a single patient with lymphoma-type ATL. The cell lines were found to be derived from HTLV-1-infected non-leukemic cells. MT-50.4 cells secreted higher levels of immunosuppressive cytokines, IL-10 and TGF-ß, expressed higher levels of Foxp3, and showed stronger suppression of CD4+CD25- T cell proliferation than MT-50.1 cells. Furthermore, the CD13 inhibitor bestatin significantly attenuated MT-50.4 cell growth, while it did not for MT-50.1 cells. These findings suggest that CD13 expression may be involved in the increased Treg-like activity of MT-50.4 cells. Hence, MT-50.4 cells will be useful for in-depth studies of CD13+Foxp3+ HTLV-1-infected cells.
Asunto(s)
Antígenos CD13 , Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Virus Linfotrópico T Tipo 1 Humano/inmunología , Leucemia-Linfoma de Células T del Adulto/inmunología , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma de Células T del Adulto/virología , Leucemia-Linfoma de Células T del Adulto/patología , Antígenos CD13/metabolismo , Infecciones por HTLV-I/inmunología , Infecciones por HTLV-I/virología , Línea CelularRESUMEN
INTRODUCTION: Human T-cell leukemia virus type 1 (HTLV-1) carriers may develop adult T-cell leukemia (ATL), or HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). The evidence is limited regarding other diseases potentially associated with HTLV-1, such as HTLV-1-associated autoimmune diseases. AREA COVERED: We summarized the available information on complications associated with HTLV-1 infection. EXPERT OPINION: Previous studies showed that HTLV-1 carriers have an increased incidence of collagen diseases including Sjögren's syndrome, as well as dysthyroidism, diabetes mellitus, and atherosclerosis. Furthermore, cognitive deficits are observed in asymptomatic carriers and in symptomatic carriers who develop HAM/TSP. It is hypothesized that altered immunoregulation occurs as a result of persistent HTLV-1 infection. A systematic review and meta-analysis demonstrated that HTLV-1 infection itself has an adverse impact on overall survival. ATL alone cannot entirely explain the adverse impact of HTLV-1 infection on overall mortality, because the incidence is low, and therefore HTLV-1-associated diseases as a whole may contribute to the inferior clinical outcome. However, there are insufficient data to determine the causal relationship between HTLV-1 infection and each complication. While non-cancerous events linked to HTLV-1 infection are not fatal, they are likely to reduce quality of life. Large prospective studies should be conducted by international collaborators.
Asunto(s)
Portador Sano , Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Paraparesia Espástica Tropical , Humanos , Enfermedades Autoinmunes/epidemiología , Portador Sano/virología , Infecciones por HTLV-I/complicaciones , Infecciones por HTLV-I/epidemiología , Leucemia-Linfoma de Células T del Adulto/epidemiología , Leucemia-Linfoma de Células T del Adulto/virología , Paraparesia Espástica Tropical/epidemiología , Paraparesia Espástica Tropical/virologíaRESUMEN
Human T-cell leukemia virus type 1 (HTLV-1) is a human delta retrovirus that causes adult T-cell leukemia/lymphoma (ATL) in 3-5% of the infected population after decades of clinical latency. HTLV-1 Tax is a potent activator of IKK/NF-κB and a clastogen. While NF-κB activities are associated with cell survival and proliferation, constitutive NF-κB activation (NF-κB hyperactivation) by Tax leads to senescence and oncogenesis. Until recently, the mechanisms underlying the DNA damage and senescence induced by Tax and NF-κB were unknown. Current data indicate that NF-κB hyperactivation by Tax causes the accumulation of a nucleic acid structure known as an R-loop. R-loop excision by the transcription-coupled nucleotide excision repair (TC-NER) endonucleases, Xeroderma pigmentosum F (XPF), and XPG, in turn, promotes DNA double-strand breaks (DSBs). NF-κB blockade prevents Tax-induced R-loop accumulation, DNA damage, and senescence. In the same vein, the silencing of XPF and XPG mitigates Tax senescence, while deficiency in either or both frequently occurs in ATL of all types. ATL cells maintain constitutively active NF-κB, accumulate R-loops, and resist Tax-induced senescence. These results suggest that ATL cells must have acquired adaptive changes to prevent senescence and benefit from the survival and proliferation advantages conferred by Tax and NF-κB. In this review, the roles of R-loops in Tax- and NF-κB-induced DNA DSBs, senescence, and ATL development, and the epigenetic and genetic alterations that arise in ATL to reduce R-loop-associated DNA damage and avert senescence will be discussed.
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Inestabilidad Genómica , Leucemia-Linfoma de Células T del Adulto , FN-kappa B , Estructuras R-Loop , Roturas del ADN de Doble Cadena , Productos del Gen tax/genética , Virus Linfotrópico T Tipo 1 Humano , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/virología , FN-kappa B/metabolismoRESUMEN
Human T cell leukemia virus type 1 (HTLV-1) was identified as the first pathogenic human retrovirus and is estimated to infect 5 to 10 million individuals worldwide. Unlike other retroviruses, there is no effective therapy to prevent the onset of the most alarming diseases caused by HTLV-1, and the more severe cases manifest as the malignant phenotype of adult T cell leukemia (ATL). MicroRNA (miRNA) dysfunction is a common feature of leukemogenesis, and it is no different in ATL cases. Therefore, we sought to analyze studies that reported deregulated miRNA expression in HTLV-1 infected cells and patients' samples to understand how this deregulation could induce malignancy. Through in silico analysis, we identified 12 miRNAs that stood out in the prediction of targets, and we performed functional annotation of the genes linked to these 12 miRNAs that appeared to have a major biological interaction. A total of 90 genes were enriched in 14 KEGG pathways with significant values, including TP53, WNT, MAPK, TGF-ß, and Ras signaling pathways. These miRNAs and gene interactions are discussed in further detail for elucidation of how they may act as probable drivers for ATL onset, and while our data provide solid starting points for comprehension of miRNAs' roles in HTLV-1 infection, continuous effort in oncologic research is still needed to improve our understanding of HTLV-1 induced leukemia.
Asunto(s)
Infecciones por HTLV-I , Leucemia-Linfoma de Células T del Adulto , MicroARNs , Biología Computacional , Infecciones por HTLV-I/genética , Virus Linfotrópico T Tipo 1 Humano , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/virología , MicroARNs/genéticaRESUMEN
B-Cell leukemia/lymphoma 11B (BCL11B) is a transcription factor important for T-cell development and acts as a tumor suppressor gene in T-cell acute lymphoblastic leukemia. Here, we identified BCL11B as a candidate leukemia-associated gene in human T-cell leukemia virus type 1 (HTLV-1)-induced adult T-cell leukemia/lymphoma (ATLL). Interestingly, the short form lacking exon 3 (BCL11B/S) protein was more highly expressed than the full-length BCL11B (BCL11B/L) in leukemic cells from most of the ATLL patients, although expression ratios of BCL11B/L to BCL11B/S were almost equal in control CD4+ T cells. BCL11B/S and BCL11B/L exhibited distinct subcellular localization and differential effects on cellular growth; BCL11B/L expression exhibited nuclear localization and inhibited cell growth in ATLL cells, whereas BCL11B/S exhibited nucleocytoplasmic distribution and accelerated cell growth. Furthermore, BCL11B/S expression accelerated the development of T-cell leukemia/lymphomas in transgenic mice carrying HTLV-1/HBZ, a critical viral factor in leukemogenesis, whereas these phenotypes did not occur in the double transgenic mice carrying BCL11B/L and HTLV-1/HBZ. In HTLV-1-infected T-cell lines, BCL11B expression is downregulated by HTLV-1/Tax, a viral factor necessary at the early stage of leukemogenesis. These results suggest that downregulation of BCL11B/L expression and upregulation of BCL11B/S may contribute to the development and progression of ATLL.
Asunto(s)
Leucemia-Linfoma de Células T del Adulto , Proteínas Represoras , Proteínas Supresoras de Tumor , Animales , Carcinogénesis/genética , Productos del Gen tax/genética , Productos del Gen tax/metabolismo , Genes Supresores de Tumor , Virus Linfotrópico T Tipo 1 Humano , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/virología , Ratones , Isoformas de Proteínas/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL), an aggressive and fatal CD4+ T-cell malignancy, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic neurological disease. Disease progression in infected individuals is the result of HTLV-1-driven clonal expansion of CD4+ T-cells and is generally associated with the activities of the viral oncoproteins Tax and Hbz. A closely related virus, HTLV-2, exhibits similar genomic features and the capacity to transform T-cells, but is non-pathogenic. In vitro, HTLV-1 primarily immortalizes or transforms CD4+ T-cells, while HTLV-2 displays a transformation tropism for CD8+ T-cells. This distinct tropism is recapitulated in infected people. Through comparative studies, the genetic determinant for this divergent tropism of HTLV-1/2 has been mapped to the viral envelope (Env). In this review, we explore the emerging roles for Env beyond initial viral entry and examine current perspectives on its contributions to HTLV-1-mediated disease development.
Asunto(s)
Productos del Gen env/genética , Productos del Gen env/metabolismo , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Leucemia-Linfoma de Células T del Adulto/virología , Internalización del Virus , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/virología , Transformación Celular Viral/genética , Productos del Gen tax/genética , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Virus Linfotrópico T Tipo 2 Humano/genética , Humanos , OncogenesRESUMEN
So far, only two retroviruses, human immunodeficiency virus (HIV) (type 1 and 2) and human T-cell lymphotropic virus type 1 (HTLV-1), have been recognized as pathogenic for humans. Both viruses mainly infect CD4+ T lymphocytes. HIV replication induces the apoptosis of CD4 lymphocytes, leading to the development of acquired immunodeficiency syndrome (AIDS). After a long clinical latency period, HTLV-1 can transform lymphocytes, with subsequent uncontrolled proliferation and the manifestation of a disease called adult T-cell leukemia (ATLL). Certain infected patients develop neurological autoimmune disorder called HTLV-1-associated myelopathy, also known as tropical spastic paraparesis (HAM/TSP). Both viruses are transmitted between individuals via blood transfusion, tissue/organ transplantation, breastfeeding, and sexual intercourse. Within the host, these viruses can spread utilizing either cell-free or cell-to-cell modes of transmission. In this review, we discuss the mechanisms and importance of each mode of transmission for the biology of HIV-1 and HTLV-1.
Asunto(s)
Linfocitos T CD4-Positivos/virología , Infecciones por VIH/transmisión , VIH-1/patogenicidad , Infecciones por HTLV-I/transmisión , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Leucemia-Linfoma de Células T del Adulto/virología , Animales , Linfocitos T CD4-Positivos/inmunología , Infecciones por HTLV-I/complicaciones , Humanos , RatonesRESUMEN
Due to the drawback of traditional and current diagnostic methods including serological and molecular assays, the development of the rapid and free-PCR techniques can be an alternative technique for the human T-cell lymphotropic virus (HTLV-1) DNA detection sequences. On the other hand, early detection of HTLV-1 prevents two dangerous diseases including Adult T-cell leukemia/lymphoma and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis. The biosensor-based methods are sensitive techniques that can provide new opportunities to detect infectious diseases, particularly in the early stage. This study provides a comparative view among recently designed biosensors for the detection of HTLV-1.
Asunto(s)
Técnicas Biosensibles/métodos , Infecciones por HTLV-I/diagnóstico , Virus Linfotrópico T Tipo 1 Humano/genética , Secuencia de Bases/genética , Infecciones por HTLV-I/genética , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/patología , Leucemia-Linfoma de Células T del Adulto/virología , Paraparesia Espástica Tropical/virología , Reacción en Cadena de la Polimerasa/métodosRESUMEN
Human T-cell leukemia virus 1 (HTLV-1) causes adult T-cell leukemia (ATL), but the mechanism underlying its initiation remains elusive. In this study, ORP4L was expressed in ATL cells but not in normal T-cells. ORP4L ablation completely blocked T-cell leukemogenesis induced by the HTLV-1 oncoprotein Tax in mice, whereas engineering ORP4L expression in T-cells resulted in T-cell leukemia in mice, suggesting the oncogenic properties and prerequisite of ORP4L promote the initiation of T-cell leukemogenesis. For molecular insight, we found that loss of miR-31 caused by HTLV-1 induced ORP4L expression in T-cells. ORP4L interacts with PI3Kδ to promote PI(3,4,5)P3 generation, contributing to AKT hyperactivation; NF-κB-dependent, p53 inactivation-induced pro-oncogene expression; and T-cell leukemogenesis. Consistently, ORP4L ablation eliminates human ATL cells in patient-derived xenograft ATL models. These results reveal a plausible mechanism of T-cell deterioration by HTLV-1 that can be therapeutically targeted.
Asunto(s)
Carcinogénesis/patología , Regulación Leucémica de la Expresión Génica , Infecciones por HTLV-I/complicaciones , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Leucemia-Linfoma de Células T del Adulto/patología , Receptores de Esteroides/metabolismo , Linfocitos T/inmunología , Animales , Apoptosis , Carcinogénesis/inmunología , Carcinogénesis/metabolismo , Proliferación Celular , Productos del Gen tax , Infecciones por HTLV-I/virología , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma de Células T del Adulto/virología , Ratones , Pronóstico , Receptores de Esteroides/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Human T cell leukemia virus type 1 (HTLV-1) mainly infects CD4+ T cells and induces chronic, persistent infection in infected individuals, with some developing adult T cell leukemia/lymphoma (ATL). HTLV-1 alters cellular differentiation, activation, and survival; however, it is unknown whether and how these changes contribute to the malignant transformation of infected cells. In this study, we used single-cell RNA-sequencing and T cell receptor-sequencing to investigate the differentiation and HTLV-1-mediated transformation of T cells. We analyzed 87,742 PBMCs from 12 infected and 3 uninfected individuals. Using multiple independent bioinformatics methods, we demonstrated the seamless transition of naive T cells into activated T cells, whereby HTLV-1-infected cells in an activated state further transformed into ATL cells, which are characterized as clonally expanded, highly activated T cells. Notably, the greater the activation state of ATL cells, the more they acquire Treg signatures. Intriguingly, the expression of HLA class II genes in HTLV-1-infected cells was uniquely induced by the viral protein Tax and further upregulated in ATL cells. Functional assays revealed that HTLV-1-infected cells upregulated HLA class II molecules and acted as tolerogenic antigen-presenting cells to induce anergy of antigen-specific T cells. In conclusion, our study revealed the in vivo mechanisms of HTLV-1-mediated transformation and immune escape at the single-cell level.
Asunto(s)
Transformación Celular Viral/inmunología , Virus Linfotrópico T Tipo 1 Humano/inmunología , Leucemia-Linfoma de Células T del Adulto/inmunología , Activación de Linfocitos , Linfocitos T/inmunología , Femenino , Productos del Gen tax/inmunología , Antígenos HLA/inmunología , Humanos , Leucemia-Linfoma de Células T del Adulto/virología , MasculinoRESUMEN
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.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Infecciones por HTLV-I/virología , Virus Linfotrópico T Tipo 1 Humano/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Infecciones por HTLV-I/inmunología , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Leucemia-Linfoma de Células T del Adulto/inmunología , Leucemia-Linfoma de Células T del Adulto/patología , Leucemia-Linfoma de Células T del Adulto/virología , Antígenos Comunes de Leucocito/metabolismo , Ratones , Infección Persistente/inmunología , Infección Persistente/virologíaRESUMEN
Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus endemic in many parts of the world. Because of migration, cases of HTLV-1 in non-HTLV-1 endemic countries have been increasingly reported. Clinical presentation of HTLV-1 infection is highly variable, with a significant risk of diagnostic delays. Skin can be the first site affected by HTLV-1-related manifestations such as cutaneous involvement of adult T-cell leukemia/lymphoma (ATLL) and infective dermatitis associated with HTLV-1. A 32-year-old Nigerian man was admitted to the infectious disease department for high fever, asthenia, lymphocytosis, and vesicular bullous lesions on both hand palms and lower limbs. After clinical work-up was performed, bacterial superinfected herpes simplex viurs-2 ulcers were the presenting sign of HTLV-1-related chronic type ATLL. Standard treatment based on interferon-α plus zidovudine was started, but it was poorly tolerated; therefore, switching to an off-label dual antiretroviral regimen was attempted. The increasing prevalence of HTLV-1 in nonendemic areas may enhance the development of alternative treatments with better efficacy and tolerability profiles.
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Leucemia-Linfoma de Células T del Adulto/patología , Neoplasias Cutáneas/patología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antivirales/uso terapéutico , Virus Linfotrópico T Tipo 1 Humano , Humanos , Interferón alfa-2/uso terapéutico , Italia , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/virología , Masculino , Nigeria/etnología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/virología , Zidovudina/uso terapéuticoRESUMEN
Viral infections are known to hijack the transcription and translation of the host cell. However, the extent to which viral proteins coordinate these perturbations remains unclear. Here we used a model system, the human T-cell leukemia virus type 1 (HTLV-1), and systematically analyzed the transcriptome and interactome of key effectors oncoviral proteins Tax and HBZ. We showed that Tax and HBZ target distinct but also common transcription factors. Unexpectedly, we also uncovered a large set of interactions with RNA-binding proteins, including the U2 auxiliary factor large subunit (U2AF2), a key cellular regulator of pre-mRNA splicing. We discovered that Tax and HBZ perturb the splicing landscape by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia/lymphoma (ATLL) samples from two independent patient cohorts, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinated by Tax and HBZ to reprogram the transcriptome.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Productos del Gen tax/metabolismo , Infecciones por HTLV-I/metabolismo , Leucemia-Linfoma de Células T del Adulto/virología , Proteínas de los Retroviridae/metabolismo , Células HEK293 , Infecciones por HTLV-I/etiología , Virus Linfotrópico T Tipo 1 Humano , Humanos , Células Jurkat , Empalme del ARN , ARN Mensajero , Factor de Empalme U2AF/metabolismoRESUMEN
Subclonal genetic heterogeneity and their diverse gene expression impose serious problems in understanding the behavior of cancers and contemplating therapeutic strategies. Here we develop and utilize a capture-based sequencing panel, which covers host hotspot genes and the full-length genome of human T-cell leukemia virus type-1 (HTLV-1), to investigate the clonal architecture of adult T-cell leukemia-lymphoma (ATL). For chronologically collected specimens from patients with ATL or pre-onset individuals, we integrate deep DNA sequencing and single-cell RNA sequencing to detect the somatic mutations and virus directly and characterize the transcriptional readouts in respective subclones. Characteristic genomic and transcriptomic patterns are associated with subclonal expansion and switches during the clinical timeline. Multistep mutations in the T-cell receptor (TCR), STAT3, and NOTCH pathways establish clone-specific transcriptomic abnormalities and further accelerate their proliferative potential to develop highly malignant clones, leading to disease onset and progression. Early detection and characterization of newly expanded subclones through the integrative analytical platform will be valuable for the development of an in-depth understanding of this disease.
Asunto(s)
Genoma Viral/genética , Virus Linfotrópico T Tipo 1 Humano/genética , Leucemia-Linfoma de Células T del Adulto/genética , Análisis de la Célula Individual/métodos , Transcriptoma/genética , Adulto , Línea Celular Tumoral , Proliferación Celular/genética , Células Cultivadas , Evolución Clonal/genética , Células Clonales/metabolismo , Células Clonales/patología , Infecciones por HTLV-I/virología , Virus Linfotrópico T Tipo 1 Humano/fisiología , Humanos , Células Jurkat , Leucemia-Linfoma de Células T del Adulto/patología , Leucemia-Linfoma de Células T del Adulto/virología , Mutación , RNA-Seq/métodos , Receptor Notch1/genética , Receptores de Antígenos de Linfocitos T/genética , Factor de Transcripción STAT3/genéticaRESUMEN
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects at least 10 million people worldwide and is associated with the development of T-cell lymphoma (TCL). The treatment of TCL remains challenging and new treatment options are urgently needed. With the goal of developing a novel therapeutic approach for TCL, we investigated the activity of the clinical formulation of oncolytic reovirus (Reolysin, Pelareorep) in TCL models. Our studies revealed that HTLV-1-negative TCL cells were highly sensitive to Reolysin-induced cell death, but HTLV-1-positive TCL cells were resistant. Consistent with these data, reovirus displayed significant viral accumulation in HTLV-1-negative cells, but failed to efficiently replicate in HTLV-1-positive cells. Transcriptome analyses of HTLV-1-positive vs. negative cells revealed a significant increase in genes associated with retroviral infection including interleukin-13 and signal transducer and activator of transcription 5 (STAT5). To investigate the relationship between HTLV-1 status and sensitivity to Reolysin, we infected HTLV-1-negative cells with HTLV-1. The presence of HTLV-1 resulted in significantly decreased sensitivity to Reolysin. Treatment with the JAK inhibitor ruxolitinib suppressed STAT5 phosphorylation and expression of the key anti-viral response protein MX1 and enhanced the anti-TCL activity of Reolysin in both HTLV-1-positive and negative cells. Our data demonstrate that the inhibition of the JAK/STAT pathway can be used as a novel approach to antagonize the resistance of HTLV-1-positive cells to oncolytic virus therapy.
Asunto(s)
Quinasas Janus/antagonistas & inhibidores , Leucemia-Linfoma de Células T del Adulto/terapia , Leucemia-Linfoma de Células T del Adulto/virología , Virus Oncolíticos/fisiología , Reoviridae/fisiología , Factor de Transcripción STAT5/antagonistas & inhibidores , Línea Celular Tumoral , Perfilación de la Expresión Génica , Virus Linfotrópico T Tipo 1 Humano , Humanos , Nitrilos/farmacología , Fosforilación , Pirazoles/farmacología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the activated NF-κB signaling pathway in ATLL is the activation of the macroautophagy (herafter referred to as autophagy in the remainder of this manuscript)-lysosomal degradation of p47 (NSFL1C), a negative regulator of the NF-κB pathway. Therefore, we considered the use of chloroquine (CQ) or hydroxychloroquine (HCQ) (CQ/HCQ) as an autophagy inhibitor to treat ATLL; these drugs were originally approved by the FDA as antimalarial drugs and have recently been used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE). In this paper, we determined the therapeutic efficacy of CQ/HCQ, as NF-κB inhibitors, in ATLL mediated by blockade of p47 degradation. Administration of CQ/HCQ to ATLL cell lines and primary ATLL cells induced cell growth inhibition in a dose-dependent manner, and the majority of cells underwent apoptosis after CQ administration. As to the molecular mechanism, autophagy was inhibited in CQ-treated ATLL cells, and activation of the NF-κB pathway was suppressed with the restoration of the p47 level. When the antitumor effect of CQ/HCQ was examined using immunodeficient mice transplanted with ATLL cell lines, CQ/HCQ significantly suppressed tumor growth and improved the survival rate in the ATLL xenograft mouse model. Importantly, HCQ selectively induced ATLL cell death in the ATLL xenograft mouse model at the dose used to treat SLE. Taken together, our results suggest that the inhibition of autophagy by CQ/HCQ may become a novel and effective strategy for the treatment of ATLL.
Asunto(s)
Cloroquina/farmacología , Hidroxicloroquina/farmacología , Factores Inmunológicos/farmacología , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , FN-kappa B/genética , Transducción de Señal/efectos de los fármacos , Proteínas Solubles de Unión al Factor Sensible a la N-Etilmaleimida/genética , Animales , Apoptosis , Autofagia , Línea Celular Tumoral , Regulación Leucémica de la Expresión Génica , Virus Linfotrópico T Tipo 1 Humano/crecimiento & desarrollo , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Humanos , Leucemia-Linfoma de Células T del Adulto/inmunología , Leucemia-Linfoma de Células T del Adulto/mortalidad , Leucemia-Linfoma de Células T del Adulto/virología , Masculino , Ratones , Ratones SCID , FN-kappa B/antagonistas & inhibidores , FN-kappa B/inmunología , Cultivo Primario de Células , Transducción de Señal/genética , Proteínas Solubles de Unión al Factor Sensible a la N-Etilmaleimida/inmunología , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Human T-cell Leukemia Virus type-1 (HTLV-1) is a retrovirus that causes two diseases including Adult T-cell Leukemia/Lymphoma (ATLL cancer) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP, a neurodegenerative disease) after a long latency period as an asymptomatic carrier (AC). There are no obvious explanations about how each of the mentioned diseases develops in the AC carriers. Finding the discriminative molecular factors and pathways may clarify the destiny of the infection. METHODS: To shed light on the involved molecular players and activated pathways in each state, differentially co-expressed modules (DiffCoEx) algorithm was employed to identify the highly correlated genes which were co-expressed differently between normal and ACs, ACs and ATLL, as well as ACs and HAM/TSP samples. Through differential pathway analysis, the dysregulated pathways and the specific disease-genes-pathways were figured out. Moreover, the common genes between the member of DiffCoEx and differentially expressed genes were found and the specific genes in ATLL and HAM/TSP were introduced as possible biomarkers. RESULTS: The dysregulated genes in the ATLL were mostly enriched in immune and cancer-related pathways while the ones in the HAM/TSP were enriched in immune, inflammation, and neurological pathways. The differential pathway analysis clarified the differences between the gene players in the common activated pathways. Eventually, the final analysis revealed the involvement of specific dysregulated genes including KIRREL2, RAB36, and KANK1 in HAM/TSP as well as LTB4R2, HCN4, FZD9, GRIK5, CREB3L4, TACR2, FRMD1, LHB, FGF3, TEAD3, GRIN2D, GNRH2, PRLH, GPR156, and CRHR2 in ATLL. CONCLUSION: The identified potential prognostic biomarkers and therapeutic targets are proposed as the most important platers in developing ATLL or HAM/TSP. Moreover, the proposed signaling network clarifies the differences between the functional players in the activated pathways in ACs, ATLL, and HAM/TSP.
Asunto(s)
Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Enfermedades Neurodegenerativas , Paraparesia Espástica Tropical , Progresión de la Enfermedad , Infecciones por HTLV-I/complicaciones , Virus Linfotrópico T Tipo 1 Humano/genética , Humanos , Leucemia-Linfoma de Células T del Adulto/virología , Enfermedades Neurodegenerativas/virología , Factores de Virulencia , Latencia del VirusRESUMEN
Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4+ T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de novo infection. Viral gene expression is induced by the transactivator protein Tax, which recruits host factors like positive transcription elongation factor b (P-TEFb) to the viral promoter. Since HTLV-1 gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8+ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, therapeutic strategies using latency reversing agents (LRAs) sought to transiently activate viral gene expression and antigen presentation of Tax to enhance CTL responses towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Here, we review strategies that aimed at enhancing Tax expression and Tax-specific CTL responses to interfere with HTLV-1 latency. Further, we provide an overview of LRAs including (1) histone deacetylase inhibitors (HDACi) and (2) activators of P-TEFb, that have mainly been studied in context of human immunodeficiency virus (HIV), but which may also be powerful in the context of HTLV-1.