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1.
Retrovirology ; 16(1): 23, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438973

RESUMO

Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other inflammatory diseases. There is no disease-specific difference in viral strains, and it is unclear how HTLV-1 causes such different diseases manifesting as lymphoproliferation or inflammation. Although some progress has been made in therapies for these diseases, the prognosis for ATL is still dismal and HAM/TSP remains an intractable disease. So far, two regulatory proteins of HTLV-1, Tax and HBZ, have been well studied and shown to have pleiotropic functions implicated in viral pathogenesis. Tax in particular can strongly activate NFκB, which is constitutively activated in HTLV-1-infected cells and considered to contribute to both oncogenesis and inflammation. However, the expression level of Tax is very low in vivo, leading to confusion in understanding its role in viral pathogenesis. A series of studies using IL-2-dependent HTLV-1-infected cells indicated that IL-10, an anti-inflammatory/immune suppressive cytokine, could induce a proliferative phenotype in HTLV-1-infected cells. In addition, type I interferon (IFN) suppresses HTLV-1 expression in a reversible manner. These findings suggest involvement of host innate immunity in the switch between lymphoproliferative and inflammatory diseases as well as the regulation of HTLV-1 expression. Innate immune responses also affect another important host determinant, Tax-specific cytotoxic T lymphocytes (CTLs), which are impaired in ATL patients, while activated in HAM/TSP patients. Activation of Tax-specific CTLs in ATL patients after hematopoietic stem cell transplantation indicates Tax expression and its fluctuation in vivo. A recently developed anti-ATL therapeutic vaccine, consisting of Tax peptide-pulsed dendritic cells, induced Tax-specific CTL responses in ATL patients and exhibited favorable clinical outcomes, unless Tax-defective ATL clones emerged. These findings support the significance of Tax in HTLV-1 pathogenesis, at least in part, and encourage Tax-targeted immunotherapy in ATL. Host innate and acquired immune responses induce host microenvironments that modify HTLV-1-encoded pathogenesis and establish a complicated network for development of diseases in HTLV-1 infection. Both host and viral factors should be taken into consideration in development of therapeutic and prophylactic strategies in HTLV-1 infection.


Assuntos
Genes pX , Infecções por HTLV-I/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Imunoterapia , Leucemia-Linfoma de Células T do Adulto/terapia , Animais , Infecções por HTLV-I/terapia , Humanos , Leucemia-Linfoma de Células T do Adulto/imunologia , Paraparesia Espástica Tropical/imunologia , Paraparesia Espástica Tropical/terapia
2.
Microb Pathog ; 135: 103566, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31252065

RESUMO

BACKGROUND: Breast cancer is one of the most common cancers in the world particularly among Iranian women. Bovine leukemia virus (BLV) is an enzootic, exogenous, and oncogenic retrovirus that causes B-cell leukosis in 1-5% of infected cattle. The current study aimed at evaluating the correlation between BLV infection and breast cancer in an Iranian population. MATERIALS AND TECHNIQUES: A total of 400 samples including 200 breast cancer-suspected tissue samples and 200 blood samples of women without breast cancer, were collected from July 2017 to October 2018 from women referred to two general hospitals in Qom Province, Iran. The nested PCR technique was performed to determine the presence of tax and gag gene of BLV in the collected samples. RESULTS: Out of 200 breast cancer-suspected tissue samples, 172 samples were malignant in terms of pathology. Other samples were reported as non-malignant and non-tumor. Based on nested PCR technique, tax and gag genes of BLV were detected in 30% and 8% of breast cancer-suspected tissue samples, respectively. The frequency of BLV in blood samples collected from women without breast cancer was 16.5% (33/200). CONCLUSION: It seems that human breast cancer and BLV infection in cattle could be associated using nested PCR technique.


Assuntos
Sangue/virologia , Mama/virologia , Infecções por Deltaretrovirus/virologia , Vírus da Leucemia Bovina/isolamento & purificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Neoplasias da Mama/sangue , Neoplasias da Mama/virologia , DNA Viral/análise , Infecções por Deltaretrovirus/epidemiologia , Feminino , Genes gag , Genes pX , Humanos , Irã (Geográfico)/epidemiologia , Vírus da Leucemia Bovina/genética , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase
3.
Blood Adv ; 3(4): 564-569, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30787019

RESUMO

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATL). The HTLV-1 viral trans-activator/oncoprotein Tax is a major driver of ATL, yet it induces rapid p21Cip1/Waf1 (p21)- and p27Kip1-mediated cellular senescence through constitutive activation (hyperactivation) of NF-κB. Although constitutive NF-κB activation is a common feature of T/B-cell leukemia/lymphoma, including ATL, it is not known how ATL cells maintain chronic NF-κB activation without undergoing senescence. Here, we demonstrate that, in contrast to HTLV-1- T-cell lines, ATL cell lines no longer undergo Tax-induced senescence. Although Tax+ and Tax- ATL cell lines showed signatures of constitutive NF-κB activation, their ability to progress through the cell cycle was unaffected. In some cases, ATL cell lines continued to proliferate despite significant upregulation of p21; additionally, many cell lines displayed altered expression of G1 and G1/S cyclins, particularly overexpression of cyclin D2. We propose that, during the course of ATL development, leukemia cells acquire genetic/epigenetic changes that can mitigate the senescence response triggered by NF-κB hyperactivation. Restoring the NF-κB-induced senescence response would likely help to control the development and progression of ATL and similar lymphoid malignancies.


Assuntos
Genes pX , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Leucemia-Linfoma de Células T do Adulto/imunologia , NF-kappa B/imunologia , Adulto , Ciclo Celular , Linhagem Celular Tumoral , Senescência Celular , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Leucemia-Linfoma de Células T do Adulto/patologia , Leucemia-Linfoma de Células T do Adulto/virologia
4.
J Hematol Oncol ; 11(1): 119, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30231940

RESUMO

BACKGROUND: HTLV-1 is a retrovirus that infects over 20 million people worldwide and is responsible for the hematopoietic malignancy adult T cell leukemia (ATL). We previously demonstrated that Notch is constitutively activated in ATL cells. Activating genetic mutations were found in Notch; however, Notch signaling was also activated in the absence of genetic mutations suggesting the existence of other mechanisms. METHODS: We analyzed the expression of Notch receptor ligands in HTLV-I-transformed cells, ATL patient-derived cell lines, and fresh uncultured ATL samples by RT-PCR, FACS, and immunohistochemistry. We then investigated viral and cellular molecular mechanisms regulating expression of JAG1. Finally, using shRNA knock-down and neutralizing antibodies, we investigated the function of JAG1 in ATL cells. RESULTS: Here, we report the overexpression of the Notch ligand, JAG1, in freshly uncultured ATL patient samples compared to normal PBMCs. We found that in ATL cells, JAG1 overexpression relies upon the viral protein Tax and cellular miR-124a, STAT3, and NFATc1. Interestingly, our data show that blockade of JAG1 signaling dampens Notch1 downstream signaling and limits cell migration of transformed ATL cells. CONCLUSIONS: Our results suggest that targeting JAG1 can block Notch1 activation in HTLV-I-transformed cells and represents a new target for immunotherapy in ATL patients.


Assuntos
Movimento Celular/fisiologia , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Proteína Jagged-1/biossíntese , Leucemia-Linfoma de Células T do Adulto/metabolismo , Receptor Notch1/metabolismo , Linhagem Celular Transformada , Transformação Celular Viral , Genes pX , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Imuno-Histoquímica , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Células Jurkat , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/patologia , Leucemia-Linfoma de Células T do Adulto/virologia , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
5.
J Virol Methods ; 260: 70-74, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30006102

RESUMO

BACKGROUND: Human T-lymphotrophic virus (HTLV) types 1 and 2 cause lifelong infection whereby most infected individuals are asymptomatic whilst a minority develop infection-related disease. These latter patients invariably have been found to have high proviral load (PVL). Therefore, infected patients are monitored by determining the proportion of lymphocytes that are infected with HTLV-1/2. An increase in PVL has been shown to represent an increasing risk of developing HTLV-associated diseases. Monitoring of PVL requires a reliable and sensitive method. In this study assays based on droplet digital PCR (ddPCR) were established and evaluated for detection and quantification of HTLV-1/2. OBJECTIVES: To develop two parallel assays to detect the tax genes and determine the PVL of HTLV-1 and -2. STUDY DESIGN: Sixty-seven clinical samples from patients infected with HTLV-1 or HTLV-2 were analysed. The samples had previously been analysed with a qPCR and a comparison between ddPCR and qPCR was performed. The specificity of the assays were determined by analyzing samples from 20 healthy blood donors. RESULTS: The ddPCR was a stable and sensitive method for detection and quantification of HTLV-1 and -2. When comparing the qPCR and ddPCR the correlation was high (Pearsons correlation coefficient 0.96). The variability of the ddPCR was very low with intra-assay coefficient of variation (CV) of 0.97-3.3% (HTLV-1) and 1.7-8.2% (HTLV-2) and inter-assay CV of 1.8-6.1% (HTLV-1) and 1.2-12.9% (HTLV-2). CONCLUSIONS: The ddPCR reliably quantified HTLV DNA in clinical samples and could be a useful tool for monitoring of PVLs in HTLV-infected individuals.


Assuntos
Infecções por HTLV-I/sangue , Infecções por HTLV-II/sangue , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Vírus Linfotrópico T Tipo 2 Humano/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , Provírus/genética , Biomarcadores/sangue , Buffy Coat/virologia , Teste em Amostras de Sangue Seco , Genes pX/genética , Infecções por HTLV-I/virologia , Infecções por HTLV-II/virologia , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 2 Humano/genética , Humanos , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Linfócitos T/virologia
6.
Neurodegener Dis ; 18(2-3): 150-155, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29990995

RESUMO

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neuroinflammatory disease related to human T lymphotropic virus type 1 (HTLV-1) infection. Interferon type III (IFN-λ), which includes IL28, IL29, and IL28R, and affects the outcome of viral infections, might be complicated in the progression of HAM/TSP. Here, we investigated the host-virus interactions in the manifestation of HAM/TSP, using IL28B, IL29, IL28R, HTLV-1 Tax, HTLV-1 basic leucine zipper factor (HBZ), and proviral load (PVL). The study groups consisted of 20 patients with HAM/TSP, 20 asymptomatic HTLV-1 carriers (ACs), and 20 healthy controls (HCs). The means of PVL, Tax, and HBZ gene expressions in the HAM/TSP group (p = 0.004, 0.006, and < 0.0001, respectively) were significantly higher than in the AC group. The comparison of IL28B, IL29, and IL28R expression in the HAM/TSP, AC, and HC groups revealed no significant difference between the first 2, but lower concentrations in the HCs (IL28B: p = 0.03, 0.01; IL29: p = 0.07, 0.01; and IL28R: p < 0.0001, respectively). In the HAM/TSP group, correlations were seen between Tax and HBZ (R = 0.61, p = 0.004) and between Tax and IL29 (R = 0.45, p = 0.04). Negative correlations were observed between Tax and IL28B (R = -0.49, p = 0.02) and between HBZ and IL28R (R = -0.43, p = 0.06). In the ACs, an inverse correlation was found between Tax and IL28B (R = -0.42, p = 0.06). These findings suggest that IL29, IL28B, and IL28R interfere in the infection of HAM/TSP, mainly via Tax activation.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Genes pX/genética , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Interleucinas/metabolismo , Receptores de Citocinas/metabolismo , Proteínas dos Retroviridae/metabolismo , Adulto , Idoso , Feminino , Humanos , Interferons/metabolismo , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica Tropical/virologia , Provírus/patogenicidade , Adulto Jovem
7.
Virology ; 520: 39-58, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29777913

RESUMO

The human T-cell leukemia virus type-1 (HTLV-1) is an oncoretrovirus that infects and transforms CD4+ T-cells and causes adult T-cell leukemia/lymphoma (ATLL) -an aggressive lymphoproliferative disease that is highly refractive to most anticancer therapies. The HTLV-1 proviral genome encodes several regulatory products within a conserved 3' nucleotide sequence, known as pX; however, it remains unclear how these factors might cooperate or dynamically interact in virus-infected cells. Here we demonstrate that the HTLV-1 latency-maintenance factor p30II induces the TP53-induced glycolysis and apoptosis regulator (TIGAR) and counters the oxidative stress, mitochondrial damage, and cytotoxicity caused by the viral oncoproteins Tax and HBZ. The p30II protein cooperates with Tax and HBZ and enhances their oncogenic potential in colony transformation/foci-formation assays. Further, we have shown that TIGAR is highly expressed in HTLV-1-induced tumors associated with oncogene dysregulation and increased angiogenesis in an in vivo xenograft model of HTLV-1-induced T-cell lymphoma. These findings provide the first evidence that p30II likely collaborates as an ancillary factor for the major oncoproteins Tax and HBZ during retroviral carcinogenesis.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Linfoma/virologia , Proteínas dos Retroviridae/metabolismo , Animais , Proteínas Reguladoras de Apoptose , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Carcinogênese , Regulação Viral da Expressão Gênica , Genes pX , Xenoenxertos , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Mitofagia , Neovascularização Patológica , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Proteínas dos Retroviridae/genética
8.
J Eur Acad Dermatol Venereol ; 32(5): 704-719, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29489036

RESUMO

The term palmoplantar keratoderma (PPK) indicates any form of persistent thickening of the epidermis of palms and soles and includes genetic as well as acquired conditions. We review the nosology of hereditary PPKs that comprise an increasing number of entities with different prognoses, and a multitude of associated cutaneous and extracutaneous features. On the basis of the phenotypic consequences of the underlying genetic defect, hereditary PPKs may be divided into the following: (i) non-syndromic, isolated PPKs, which are characterized by a unique or predominant palmoplantar involvement; (ii) non-syndromic PPKs with additional distinctive cutaneous and adnexal manifestations, here named complex PPKs; (iii) syndromic PPKs, in which PPK is associated with specific extracutaneous manifestations. To date, the diagnosis of the different hereditary PPKs is based mainly on clinical history and features combined with histopathological findings. In recent years, the exponentially increasing use of next-generation sequencing technologies has led to the identification of several novel disease genes, and thus substantially contributed to elucidate the molecular basis of such a heterogeneous group of disorders. Here, we focus on hereditary non-syndromic isolated and complex PPKs. Syndromic PPKs are reviewed in the second part of this 2-part article, where other well-defined genetic diseases, which may present PPK among their phenotypic manifestations, are also listed and diagnostic and therapeutic approaches for PPKs are summarized.


Assuntos
Queratinas/genética , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Antígenos Ly/genética , Proteínas Reguladoras de Apoptose , Aquaporina 5/genética , Proteínas de Transporte/genética , Colágeno/genética , Conexina 43/genética , Desmogleína 1/genética , Desmoplaquinas/genética , Genes pX/genética , Glicoproteínas/genética , Humanos , Ceratodermia Palmar e Plantar/classificação , Metaloendopeptidases/genética , Fenótipo , Serpinas/genética , Canais de Cátion TRPV/genética , Proteínas Supressoras de Tumor/genética , Ativador de Plasminogênio Tipo Uroquinase/genética
9.
Virus Res ; 228: 1-6, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27845163

RESUMO

BACKGROUND: Previous studies have suggested debatable roles of Tax and HBZ gene expression in the pathogenesis of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In this study, HTLV-1 and host interactions in the manifestation of HAM/TSP were evaluated. METHODS: A cross-sectional study was conducted on 33 HAM/TSP patients and 38 HTLV-1 asymptomatic carriers (ACs). HTLV-1-Tax, HBZ gene expression, and proviral load (PVL) were assessed using the quantitative real-time PCR (TaqMan), host plasma neopterin level, and HLA-I, and the clinical manifestation were evaluated. RESULTS: The HTLV-1 PVLs in HAM/TSP and ACs were 306±360.741 copies/104 PBMCs and 250.98±629.94 copies/104 PBMCs, respectively; the PVL was higher in HAM/TSP than that in ACs (p=0.004). HTLV-1 Tax and HBZ expression in HAM/TSP was higher than that in ACs, wherein only the Tax expression was statistically significant (p=0.039). In contrast to Japanese HTLV-1-infected subjects, HLA-A*02, HLA-A*24, HLA-Cw*08, and HLA-B*5401 did not exhibit preventive effects for HAM/TSP manifestation. The plasma neopterin level was significantly higher in HAM/TSPs than that in ACs; furthermore, there was a strong significant correlation between plasma neopterin and PVL (R=0.76, p=0.001). Moreover, there were significant correlation between urinary disturbances and haematological indices, including the RBC count (R=-0.61, p=0.01) and Hematocrit (Ht) index (R=-0.75, p=0.002), and between mobility disturbances with Tax expression (R=-0.58, p=0.02) and WBC counts (R=-0.54, p=0.04), and finally, a significant association was found between the sensory disturbances and PVL (p=0.05). CONCLUSION: Overall, HTLV-1 PVL and Tax may be the valid predictors of disease development, and the neopterin level may be a valid predictor of disease progression. In addition, Tax and neopterin are more helpful than PVL for the monitoring of HTLV-1-infected patients.


Assuntos
Genes MHC Classe I , Infecções por HTLV-I/genética , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Neopterina/sangue , Paraparesia Espástica Tropical/diagnóstico , Paraparesia Espástica Tropical/etiologia , Adulto , Fatores de Transcrição de Zíper de Leucina Básica/genética , Contagem de Células Sanguíneas , Estudos Transversais , Índices de Eritrócitos , Feminino , Regulação Viral da Expressão Gênica , Genes pX , Infecções por HTLV-I/sangue , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Provírus/genética , Proteínas dos Retroviridae/genética , Avaliação de Sintomas , Carga Viral , Fatores de Virulência/genética
11.
Retrovirology ; 13(1): 56, 2016 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-27519553

RESUMO

BACKGROUND: Virus transmission from various wild and domestic animals contributes to an increased risk of emerging infectious diseases in human populations. HTLV-1 is a human retrovirus associated with acute T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 originated from ancient zoonotic transmission from nonhuman primates, although cases of zoonotic infections continue to occur. Similar to HTLV-1, the simian counterpart, STLV-1, causes chronic infection and leukemia and lymphoma in naturally infected monkeys, and combined are called primate T-lymphotropic viruses (PTLV-1). However, other clinical syndromes typically seen in humans such as a chronic progressive myelopathy have not been observed in nonhuman primates. Little is known about the development of neurologic and inflammatory diseases in human populations infected with STLV-1-like viruses following nonhuman primate exposure. RESULTS: We performed detailed laboratory analyses on an HTLV-1 seropositive patient with typical HAM/TSP who was born in Liberia and now resides in the United States. Using a novel droplet digital PCR for the detection of the HTLV-1 tax gene, the proviral load in PBMC and cerebrospinal fluid cells was 12.98 and 51.68 %, respectively; however, we observed a distinct difference in fluorescence amplitude of the positive droplet population suggesting possible mutations in proviral DNA. A complete PTLV-1 proviral genome was amplified from the patient's PBMC DNA using an overlapping PCR strategy. Phylogenetic analysis of the envelope and LTR sequences showed the virus was highly related to PTLV-1 from sooty mangabey monkeys (smm) and humans exposed via nonhuman primates in West Africa. CONCLUSIONS: These results demonstrate the patient is infected with a simian variant of PTLV-1, suggesting for the first time that PTLV-1smm infection in humans may be associated with a chronic progressive neurologic disease.


Assuntos
Infecções por Deltaretrovirus/complicações , Infecções por Deltaretrovirus/virologia , Paraparesia Espástica Tropical/virologia , Vírus Linfotrópico T Tipo 1 de Primatas/isolamento & purificação , África Ocidental , Idoso , Animais , Infecções por Deltaretrovirus/transmissão , Genes pX , Haplorrinos/virologia , Humanos , Leucócitos Mononucleares/virologia , Masculino , Filogenia , Reação em Cadeia da Polimerase , Vírus Linfotrópico T Tipo 1 de Primatas/genética , Vírus Linfotrópico T Tipo 1 de Primatas/patogenicidade , Provírus/genética
12.
Prev Vet Med ; 129: 9-12, 2016 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-27317318

RESUMO

Enzootic bovine leucosis is an infectious disease caused by Bovine leukemia virus (BLV) and is well described in bovines. The majority of infected animals are asymptomatic, one to five percent develop lymphoma and from 30 to 50% present a persistent lymphocytosis. The virus occurs naturally in cattle and experimentally in buffaloes, capybaras and rabbits. The occurrence of lymphoma in buffaloes has been attributed to BLV infection by some authors in India and Venezuela, but not confirmed by other studies and little information on natural BLV infection in buffaloes is available. The aim of this study was to evaluate the occurrence of BLV in a sub-sample of buffalo from Amazon and southeast regions in Brazil. Three hundred and fifteen serum samples were negative using commercial AGID and ELISA (ELISA-gp51) which detect anti-BLV glycoprotein gp51 antibodies. The same samples were also evaluated for antibodies to whole virus through a commercial ELISA (ELISA-BLV) in which 77 (24.44%) were found seropositive and two (0.63%) inconclusive. On the other hand, all animals were negative by PCR to BLV targeted to the env and tax genes. These results suggest that ELISA-BLV produces false positive results in buffalo serum (p<0.001). In addition, one buffalo lymphoma sample was negative in both PCR assays used in this study. BLV was not detected in buffaloes from the Amazon basin and the southeast region of Brazil. Serological tests, like ELISA-BLV, usually used for cattle may produce false-positive results for BLV in buffaloes and direct detection tests such as PCR should be chosen in these surveys. The occurrence of lymphoma in buffalo was not associated with BLV infection in the one case analyzed in this work and the etiology and pathogenesis of this disease should be clarified.


Assuntos
Búfalos , Leucose Enzoótica Bovina/diagnóstico , Vírus da Leucemia Bovina/imunologia , Vírus da Leucemia Bovina/isolamento & purificação , Animais , Anticorpos Antivirais/sangue , Brasil , Bovinos , DNA Viral/sangue , Leucose Enzoótica Bovina/sangue , Ensaio de Imunoadsorção Enzimática/veterinária , Reações Falso-Negativas , Genes env , Genes pX , Imunodifusão/métodos , Linfoma/etiologia , Linfoma/veterinária , Reação em Cadeia da Polimerase/veterinária
13.
Acta Virol ; 59(3): 247-56, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26435148

RESUMO

Human T lymphotropic virus 1 (HTLV-1) is a pathogenic retrovirus that spreads predominantly via cell-to-cell contact. Two models of cell-to-cell virus transmission are proposed: virological synapse (VS) and viral biofilms (VB). Both infectious structures can be involved in transmission and synergistically enhance HTLV-1 spread between cells. Although transmission of virus via VB has been reported, the molecular composition of VB remains poorly understood. In this study we generated new anti-VB monoclonal antibodies (MAbs) and screenedthem along with a panel of anti-human cluster of differentiation (CD) MAbs to select antigens associated with VB. Among four MAbs generated against VB, two MAbs were identified as anti-CD25 (IL-2RA). We found that antigens CD4, CD150, CD25, CD70, and CD80 were enriched in VB. We also determined that expression of viral protein Tax, a central molecule in HTLV-1 transmission, upregulates intercellular adhesion molecule 1 (ICAM-1), CD95, CD25, CD70, and CD80. Whether these antigens are essential for VB formation and HTLV-1 infection remains unknown and will be determined in further experiments.


Assuntos
Anticorpos Monoclonais/biossíntese , Biofilmes , Infecções por HTLV-I/transmissão , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Transformação Celular Viral , Genes pX/fisiologia , Células HEK293 , Humanos
14.
Retrovirology ; 12: 71, 2015 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-26265053

RESUMO

BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive and fatal malignancy of CD4(+) T-lymphocytes infected by the Human T-Cell Virus Type 1 (HTLV-1). The molecular mechanisms of transformation in ATLL have not been fully elucidated. However, genomic instability and cumulative DNA damage during the long period of latency is believed to be essential for HTLV-1 induced leukemogenesis. In addition, constitutive activation of the NF-κB pathway was found to be a critical determinant for transformation. Whether a connection exists between NF-κB activation and accumulation of DNA damage is not clear. We recently found that the HTLV-1 viral oncoprotein, Tax, the activator of the NF-κB pathway, induces DNA double strand breaks (DSBs). RESULTS: Here, we investigated whether any of the NF-κB target genes are critical in inducing DSBs. Of note, we found that inducible nitric oxide synthase (iNOS) that catalyzes the production of nitric oxide (NO) in macrophages, neutrophils and T-cells is over expressed in HTLV-1 infected and Tax-expressing cells. Interestingly, we show that in HTLV-1 infected cells, iNOS expression is Tax-dependent and specifically requires the activation of the classical NF-κB and JAK/STAT pathways. A dramatic reduction of DSBs was observed when NO production was inhibited, indicating that Tax induces DSBs through the activation of NO synthesis. CONCLUSIONS: Determination of the impact of NO on HTLV-1-induced leukemogenesis opens a new area for treatment or prevention of ATLL and perhaps other cancers in which NO is produced.


Assuntos
Quebras de DNA de Cadeia Dupla , Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/virologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Adulto , Amidinas/farmacologia , Cumarínicos/farmacologia , Regulação da Expressão Gênica , Genes pX , Infecções por HTLV-I/genética , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Janus Quinases/metabolismo , Células Jurkat , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Ativação Transcricional , Células Tumorais Cultivadas
15.
Rinsho Ketsueki ; 56(7): 815-24, 2015 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-26251144

RESUMO

ATL is an aggressive T-cell malignancy caused by HTLV-1 virus infection. Tax, which is the most important regulatory protein of HTLV-1, is associated with aggressive proliferation of host cells and is also a major target antigen for CD8⁺ cytotoxic T-cells (CTLs). Recently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has proven effective for ATL, and donor-derived Tax-specific CTL might contribute to graft-versus-ATL effects in some recipients who maintained complete remission after allo-HSCT. We, for the first time, analyzed the Tax-specific T-cell receptor (TCR) repertoire, phenotypes and functions of Tax-specific CTLs at single-cell levels in HLA-A24⁺ ATL patients who underwent allo-HSCT. We found that 1) a particular amino acid sequence motif (PDR) in the CDR3 region of TCR-ß was conserved in different patients and also within the same patient before and after allo-HSCT, and 2) the PDR⁺ Tax-specific CTL clone selectively expanded in ATL long-term survivors as less-differentiated effector memory CTLs. Actually, the PDR⁺ CTL showed not only strong binding activity for the Tax-tetramer but also strong killing activity against patients' HTLV-1-infected T-cells without any reaction against normal cells. We are presently evaluating the killing activities of PDR⁺ TCR-transduced T-cells against Tax in immunodeficient mice, with the aim of developing a new immunotherapy for ATL.


Assuntos
Genes pX , Imunoterapia , Leucemia-Linfoma de Células T do Adulto/terapia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Aloenxertos , Animais , Infecções por HTLV-I , Transplante de Células-Tronco Hematopoéticas , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/imunologia , Receptores de Antígenos de Linfócitos T/imunologia
16.
PLoS Pathog ; 11(3): e1004721, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25774694

RESUMO

Persistent activation of NF-κB by the Human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, Tax, is vital for the development and pathogenesis of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). K63-linked polyubiquitinated Tax activates the IKK complex in the plasma membrane-associated lipid raft microdomain. Tax also interacts with TAX1BP1 to inactivate the NF-κB negative regulatory ubiquitin-editing A20 enzyme complex. However, the molecular mechanisms of Tax-mediated IKK activation and A20 protein complex inactivation are poorly understood. Here, we demonstrated that membrane associated CADM1 (Cell adhesion molecule1) recruits Ubc13 to Tax, causing K63-linked polyubiquitination of Tax, and IKK complex activation in the membrane lipid raft. The c-terminal cytoplasmic tail containing PDZ binding motif of CADM1 is critical for Tax to maintain persistent NF-κB activation. Finally, Tax failed to inactivate the NF-κB negative regulator ubiquitin-editing enzyme A20 complex, and activate the IKK complex in the lipid raft in absence of CADM1. Our results thus indicate that CADM1 functions as a critical scaffold molecule for Tax and Ubc13 to form a cellular complex with NEMO, TAX1BP1 and NRP, to activate the IKK complex in the plasma membrane-associated lipid rafts, to inactivate NF-κB negative regulators, and maintain persistent NF-κB activation in HTLV-1 infected cells.


Assuntos
Moléculas de Adesão Celular/metabolismo , Infecções por Deltaretrovirus/metabolismo , Genes pX/fisiologia , Imunoglobulinas/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Animais , Molécula 1 de Adesão Celular , Cisteína Endopeptidases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Vírus Linfotrópico T Tipo 1 Humano , Humanos , Immunoblotting , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células Jurkat , Camundongos , Camundongos Knockout , Microscopia Confocal , Proteínas Nucleares/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Enzimas de Conjugação de Ubiquitina/metabolismo
18.
Cancer Res ; 74(21): 6082-93, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25205102

RESUMO

Viruses disrupt the host cell microRNA (miRNA) network to facilitate their replication. Human T-cell leukemia virus type I (HTLV-1) replication relies on the clonal expansion of its host CD4(+) and CD8(+) T cells, yet this virus causes adult T-cell leukemia/lymphoma (ATLL) that typically has a CD4(+) phenotype. The viral oncoprotein Tax, which is rarely expressed in ATLL cells, has long been recognized for its involvement in tumor initiation by promoting cell proliferation, genetic instability, and miRNA dysregulation. Meanwhile, HBZ is expressed in both untransformed infected cells and ATLL cells and is involved in sustaining cell proliferation and silencing virus expression. Here, we show that an HBZ-miRNA axis promotes cell proliferation and genetic instability, as indicated by comet assays that showed increased numbers of DNA-strand breaks. Expression profiling of miRNA revealed that infected CD4(+) cells, but not CD8(+) T cells, overexpressed oncogenic miRNAs, including miR17 and miR21. HBZ activated these miRNAs via a posttranscriptional mechanism. These effects were alleviated by knocking down miR21 or miR17 and by ectopic expression of OBFC2A, a DNA-damage factor that is downregulated by miR17 and miR21 in HTLV-1-infected CD4(+) T cells. These findings extend the oncogenic potential of HBZ and suggest that viral expression might be involved in the remarkable genetic instability of ATLL cells.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Proliferação de Células/genética , Instabilidade Genômica , Leucemia-Linfoma de Células T do Adulto/genética , Proteínas Virais/genética , Adulto , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Regulação Viral da Expressão Gênica , Genes pX/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Leucemia-Linfoma de Células T do Adulto/imunologia , Leucemia-Linfoma de Células T do Adulto/patologia , Proteínas dos Retroviridae , Proteínas Virais/metabolismo
19.
Int J Dermatol ; 53(9): 1111-3, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24962725

RESUMO

OBJECTIVE: Progressive symmetric erythrokeratodermia (PSEK) is characterized by symmetric and growing erythematous hyperkeratotic patches over the body shortly after birth, particularly trunk and limbs, the buttocks, and the face, sometimes together with palmoplantar keratoderma (PPK). The GJB2, GJB3, GJB4, GJB6, ARS (Component B), and LOR gene mutation might contribute to PSEK manifestation. This study aimed to identify sequence alteration of these genes in a Chinese PSEK patient with pseudoainhum. METHODS: Genomic DNA was purified from the patient's peripheral blood. Mutation analysis of target genes was performed by direct sequencing using ABI 3730 sequencer RESULTS: No exonic mutations was identified in the aforementioned genes. CONCLUSIONS: The result underlines the genetic heterogeneity of PSEK and other related erythrokeratodermas.


Assuntos
Ainhum/genética , Constrição Patológica/genética , Eritroceratodermia Variável/genética , Adolescente , Antígenos Ly/genética , Grupo com Ancestrais do Continente Asiático/genética , China , Conexina 26 , Conexina 30 , Conexinas/genética , Genes pX/genética , Humanos , Masculino , Mutação , Análise de Sequência de DNA , Ativador de Plasminogênio Tipo Uroquinase/genética
20.
Biomed Res Int ; 2014: 902478, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24791004

RESUMO

Adult T cell leukemia (ATL) is a malignant lymphoproliferative disease caused by human T cell leukemia virus type I (HTLV-I). To develop an effective therapy against the disease, we have examined the oncolytic ability of an attenuated vaccinia virus (VV), LC16m8Δ (m8Δ), and an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) line, 4O1/C8, against an HTLV-I-infected rat T cell line, FPM1. Our results demonstrated that m8Δ was able to replicate in and lyse tumorigenic FPM1 cells but was incompetent to injure 4O1/C8 cells, suggesting the preferential cytolytic activity toward tumor cells. To further enhance the cytolysis of HTLV-I-infected cells, we modified m8Δ and obtained m8Δ/RT1AlSCTax180L, which can express a single chain trimer (SCT) of rat major histocompatibility complex class I with a Tax-epitope. Combined treatment with m8Δ/RT1AlSCTax180L and 4O1/C8 increased the cytolysis of FPM1V.EFGFP/8R cells, a CTL-resistant subclone of FPM1, compared with that using 4O1/C8 and m8Δ presenting an unrelated peptide, suggesting that the activation of 4O1/C8 by m8Δ/RT1AlSCTax180L further enhanced the killing of the tumorigenic HTLV-I-infected cells. Our results indicate that combined therapy of oncolytic VVs with SCTs and HTLV-I-specific CTLs may be effective for eradication of HTLV-I-infected cells, which evade from CTL lysis and potentially develop ATL.


Assuntos
Genes pX/genética , Infecções por HTLV-I/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas Sintéticas/imunologia , Vírus Vaccinia/genética , Vacinas Virais/imunologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Infecções por HTLV-I/prevenção & controle , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/genética , Interferon gama/análise , Interferon gama/imunologia , Interferon gama/metabolismo , Ratos , Vacinas Sintéticas/genética , Vacinas Sintéticas/metabolismo , Vacinas Sintéticas/farmacologia , Vírus Vaccinia/imunologia , Vacinas Virais/genética , Vacinas Virais/metabolismo , Vacinas Virais/farmacologia
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