RESUMO
Adult T cell leukemia/lymphoma is a malignancy with a poor prognosis caused by human T lymphocyte virus type 1 (HTLV-1) infection. Tax and HBZ are two major viral proteins that may be involved in oncogenesis by disrupting apoptosis. Because Bcl-xL plays an integral role in the anti-apoptotic pathway, this study examines the interaction between host apoptosis and oncoproteins. We investigated 37 HTLV-1-infected individuals, including 18 asymptomatic and 19 adult T cell leukemia/lymphoma (ATLL) subjects. mRNA was extracted and converted to cDNA from peripheral blood mononuclear cells, and then gene expression was determined using TaqMan q-PCR. Moreover, the HTLV-1 proviral load (PVL) was also measured using a commercial absolute quantification kit (Novin Gene, Iran). Data analysis revealed that the mean of TAX, HBZ, and PVL was significantly higher among the study groups (ATLL and carrier groups p = .003, p = .000, and p = .002 respectively). There was no statistical difference in Bcl-xL gene expression between the study groups (p = .323). It is proposed that this anti-apoptotic pathway may not be directly involved in the development of ATLL lymphoma. Bcl-xL, TAX, HBZ gene expression, and PVL can be utilized as prognostic markers.
Assuntos
Infecções por HIV , Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto , Linfoma , Adulto , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Leucócitos Mononucleares , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Proteínas dos Retroviridae/genética , Proteínas dos Retroviridae/metabolismo , Infecções por HIV/patologia , Linfoma/patologia , Expressão Gênica , Produtos do Gene tax/genética , Produtos do Gene tax/metabolismoRESUMO
Human T lymphotropic virus (HTLV-I) is a retrovirus that has been recognized as a causative agent of two crucidal diseases, HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) and Adult T cell Leukemia-Lymphoma (ATLL). The virus not only induces those diseases in a small proportion of HTLV-I carriers (3-5%) but also it is associated with other diseases such as HTLV-I-Associated Arthropathy (HAAP), Cutaneous T Cell Lymphoma (CTCL), Graves' disease, uveitis, polymyositis, chronic respiratory diseases, lymphadenitis and dermatitis. Furthermore, HTLV related and accelerated disorders were more investigated, and the factors that might implicate in the development or progression of diseases have been discussed. We founded 13 categories of non-associated disease in studies such as Reproductive Disorders, Coronary Artery Disease (CAD), non -ATLL lymphoma, Co-infection, non-HAM/TSP neurological associated disease, non ATLL cutaneous associated disease, Autoimmune-Inflammatory related disease, Kidney disease, Liver disease, Respiratory disease, TB disease and Thyroid disease. With regard to the reviewed studies suggested HTLV-I disorders can divide into three manifests; related, accelerated and associated disease. However, interaction between HTLV-I infection and host immune response was complicated and vague. Some infectious patients indicated the involvement of inflammatory response of immune system, but in other individuals function of anti-inflammatory elements was observed. For a better understanding of this classification, more systematic studies should be designed and need to provide a global network to control and prevent HTLV affiliated diseases.
Assuntos
Doenças Autoimunes , Infecções por Deltaretrovirus , Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto , Paraparesia Espástica Tropical , Adulto , Humanos , Paraparesia Espástica Tropical/complicações , Pele/patologiaRESUMO
BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder of HTLV-1-host interactions in infected TCD4+ cells. In this study, the HTLV-1 proviral load (PVL) and HBZ as viral elements and AKT1, BAD, FOXP3, RORγt and IFNλ3 as the host factors were investigated. METHODS: The study was conducted in ATLLs, HTLV-1-associated myelopathy/tropical spastic paraparesis patients (HAM/TSPs) and HTLV-1-asympthomatic carriers (ACs). The DNA and mRNA from peripheral blood mononuclear cells were extracted for gene expression assessments via qRT-PCR, TaqMan assay, and then confirmed by western blotting. RESULTS: As it was expected, the HTLV-1-PVL were higher in ATLLs than ACs (P = 0.002) and HAM/TSP (P = 0.041). The HBZ expression in ATLL (101.76 ± 61.3) was radically higher than in ACs (0.12 ± 0.05) and HAM/TSP (0.01 ± 0.1) (P = 0.001). Furthermore, the AKT1 expression in ATLLs (13.52 ± 4.78) was higher than ACs (1.17 ± 0.27) (P = 0.05) and HAM/TSPs (0.72 ± 0.49) (P = 0.008). However, BAD expression in ATLL was slightly higher than ACs and HAM/TSPs and not significant. The FOXP3 in ATLLs (41.02 ± 24.2) was more than ACs (1.44 ± 1) (P = 0.007) and HAM/TSP (0.45 ± 0.15) (P = 0.01). However, RORγt in ATLLs (27.43 ± 14.8) was higher than ACs (1.05 ± 0.32) (P = 0.02) but not HAM/TSPs. Finally, the IFNλ3 expression between ATLLs (31.92 ± 26.02) and ACs (1.46 ± 0.63) (P = 0.01) and ACs and HAM/TSPs (680.62 ± 674.6) (P = 0.02) were statistically different, but not between ATLLs and HAM/TSPs. CONCLUSIONS: The present and our previous study demonstrated that HTLV-1-PVL and HBZ and host AKT1 and Rad 51 are novel candidates for molecular targeting therapy of ATLL. However, high level of RORγt may inhibit Th1 response and complicated in ATLL progressions.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Infecções por HTLV-I/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Leucemia-Linfoma de Células T do Adulto/genética , Proteínas dos Retroviridae/genética , Adulto , Feminino , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica/genética , Infecções por HTLV-I/sangue , Infecções por HTLV-I/patologia , Infecções por HTLV-I/virologia , Interações Hospedeiro-Patógeno/genética , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Leucemia-Linfoma de Células T do Adulto/sangue , Leucemia-Linfoma de Células T do Adulto/patologia , Leucemia-Linfoma de Células T do Adulto/virologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Paraparesia Espástica Tropical/sangue , Paraparesia Espástica Tropical/genética , Paraparesia Espástica Tropical/patologia , Paraparesia Espástica Tropical/virologia , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/genética , Rad51 Recombinase/genética , Células Th1 , Carga Viral , Proteína de Morte Celular Associada a bcl/genéticaRESUMO
Adult T cell leukemia/lymphoma (ATLL) is a life-threatening malignancy of HTLV-1 infected Th lymphocytes. In the present study host-virus interactions were investigated by assessment of HTLV-1 proviral load (PVL) and host gene expression. A cross-sectional study was carried out on 18 ATLL, 10 HAM/TSP patients and 18 HTLV-1 asymptomatic carriers (ACs). DNA and mRNA of the peripheral blood mononuclear cells were extracted for PVL and LAT, BIM, c-FOS and RAD51 gene expression measurement using qRT-PCR. The mean PVL in ATLL patients was 11,430 ± 3770 copies/104 which was statistically higher than ACs, 530 ± 119 copies/104, (p < 0.001). The expression of BIM, and c-FOS in ATLL patients were higher than HTLV-1 ACs; however, there were no statistically significant differences. The expression of RAD51 as an essential player on DNA repair showed around 160 times increase in ATLL group (166 ± 95) compared to ACs (1.04 ± 0.34) which is statistically significant (p < 0.001). Interestingly, there was a positive correlation between RAD51 expression and HTLV-PVL. The expression of LAT as a central adaptor in TCR signaling interestingly was around 36 times higher in ATLL group than ACs (ATLL; 41.33 ± 19.91 vs. ACs; 1.15 ± 0.22, p < 0.001). This finding showed that TCR signaling pathway mainly provides the growth factors for transformed cells. Furthermore, the overexpression of RAD51 which has been induced in HTLV-1 infected cells as a consequence of virus replication is not able to overcome the DNA damage toward cell transformation.