transforming-growth-factor-beta and HTLV-I-Infections

Human T-lymphotropic virus type 1 (HTLV-1) infection is associated with the clonal expansion and transformation of mature T lymphocytes. While the mechanisms involved are incompletely understood the viral regulatory protein Tax plays a central role in these processes. Recent studies employing genomic and proteomic approaches have demonstrated the marked complexity of gene deregulation associated with Tax expression and confirmed the remarkable pleiotropism of this protein as evidenced by the numerous Tax-cellular protein interactions in infected cells. In this review, we summarize the role of Tax in the deregulation of selected cellular-signaling pathways. Specifically, this has focused on the influence and interaction of Tax with the AP-1 and NF-AT transcription factors, PDZ domain-containing proteins, Rho-GTPases, and the Janus kinase/signal transducer and activator of transcription and transforming growth factor-beta-signaling pathways. In addition to identifying the deregulation of events within these pathways, attempts have been made to highlight differences between HTLV-1 and -2, which may relate to differences in their pathogenic properties.

Topics: Gene Expression Regulation, Viral; Gene Products, tax; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Signal Transduction; T-Lymphocytes; Transcription, Genetic; Transforming Growth Factor beta

Viral oncoprotein Tax plays key roles in transformation of human T-cell leukemia virus (HTLV-1)-infected T cells leading to adult T-cell leukemia (ATL), and is the key antigen recognized during HTLV-associated myelopathy (HAM). In HLA-A2+ asymptomatic carriers as well as ATL and HAM patients, Tax(11-19) epitope exhibits immunodominance. Here, we evaluate CD8 T-cell immune response against this epitope in the presence and absence of dendritic cells (DCs) given the recent encouraging observations made with Phase 1 DC-based vaccine trial for ATL. To facilitate these studies, we first generated an HLA-A2/DTR hybrid mouse strain carrying the HLA-A2.1 and CD11c-DTR genes. We then studied CD8 T-cell immune response against Tax(11-19) epitope delivered in the absence or presence of Freund's adjuvant and/or DCs. Overall results demonstrate that naturally presented Tax epitope could initiate an antigen-specific CD8T cell response in vivo but failed to do so upon DC depletion. Presence of adjuvant potentiated Tax(11-19)-specific response. Elevated serum IL-6 levels coincided with depletion of DCs whereas decreased TGF-β was associated with adjuvant use. Thus, Tax(11-19) epitope is a potential candidate for the DC-based anti-HTLV-1 vaccine and the newly hybrid mouse strain could be used for investigating DC involvement in human class-I-restricted immune responses.

Topics: Animals; CD8-Positive T-Lymphocytes; Dendritic Cells; Female; Gene Products, tax; HLA-A2 Antigen; HTLV-I Infections; Immunodominant Epitopes; Interleukin-6; Male; Mice, Inbred C57BL; Mice, Transgenic; Transforming Growth Factor beta; Viral Vaccines

The aim of this study was to show the clinical and pathological characteristics of anti-centromere-antibody (ACA)-seropositive Sjögren's syndrome (SS) in two anti-human T-cell leukemia virus type I (HTLV-I)-seropositive patients.. One patient was an HTLV-I carrier whereas the other was diagnosed with HTLV-I-associated myelopathy (HAM). Background data including serum HTLV-I titers, viral loads, and cytokine profiles were recorded. Azocarmine with aniline blue (Azan)-Mallory staining and immunohistochemistry of the labial salivary glands (LSGs) and a muscle biopsy specimen from the HAM patient were performed.. Serum transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), and HTLV-I viral load were high in the HAM-SS patient compared with the HTLV-I carrier. Fibrous change in LSG was prominent in the HAM-SS patient. Although TGF-β expression was similar in the two patients, expression of HTLV-I-related proteins including p12, p28, group-specific antigen (GAG), and nuclear factor kappa-B (NF-κB) in the LSG were dominantly detected in the HAM-SS patient. Frequency of TGF-β staining in HTLV-I-seropositive SS patients without ACA, HTLV-I-seronegative SS patients with ACA, and HTLV-I-seronegative SS patients without ACA was lower than that of the previous two patients.. A high HTLV-I viral load in situ is supposed to promote the production of cytokines, especially TGF-β, resulting in the fibrous change of LSG in ACA-seropositive SS patients.

Topics: Antibodies, Antinuclear; Biomarkers; Carrier State; Centromere; Female; Fibrosis; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Lip; Middle Aged; Mouth Mucosa; Muscle, Skeletal; Salivary Glands, Minor; Sjogren's Syndrome; Transforming Growth Factor alpha; Transforming Growth Factor beta; Viral Load; Viral Proteins; Xerostomia

Adult T-cell leukaemia-lymphoma (ATLL) is an aggressive malignancy of CD4(+)  CD25(+) T lymphocytes, characterized by a severely compromised immunosystem, in which the human T-cell lymphotropic virus type 1 (HTLV-1) has been recognized as the aetiological agent. This study found that an IκB kinase β (IKKβ) inhibitor Bay11-7082 inactivated mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 and transcription factor nuclear factor-κB in HTLV-1-infected T cells; this was significantly enhanced in the presence of the mTOR inhibitor everolimus. In addition, Bay11-7082 decreased production of the immunosuppressive cytokine interleukin-10 (IL-10), which was further down-regulated when Bay11-7082 was combined with evelolimus in HTLV-1-infected T and ATLL cells isolated from patients. Interleukin-10 is known to inhibit maturation and the antigen-presenting function of dendritic cells (DCs). The culture media of HTLV-1-infected MT-1 cells, which contained a large amout of IL-10, hampered tumour necrosis factor-α-induced maturation of DCs isolated from healthy volunteers. Culture supernatant of MT-1 cells treated with a combination of Bay11-7082 and everolimus augmented maturation of DCs in association with a decrease in production of IL-10 and enhanced the allostimulatory function of DCs. Similarly, when DCs isolated from patients with ATLL were treated with the combination of Bay11-7082 and everolimus, they were fully matured and their capability to stimulate proliferation of lymphocytes was augmented. Taken together, the combination of Bay11-7082 and everolimus might exhibit immunostimulatory properties in HTLV-1-infected T and ATLL cells isolated from patients, and this combination may be potentially therapeutic to regain the compromised immunosystem in ATLL patients.

Topics: Antineoplastic Agents; Cell Line; Dendritic Cells; Everolimus; Gene Expression Regulation; HTLV-I Infections; Humans; I-kappa B Kinase; Interleukin-10; Lymphocyte Culture Test, Mixed; Monocytes; Nitriles; Signal Transduction; Sirolimus; STAT3 Transcription Factor; Sulfones; T-Lymphocytes; TOR Serine-Threonine Kinases; Transforming Growth Factor beta

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is etiologically associated with adult T-cell leukemia. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the provirus, is involved in both regulation of viral gene transcription and T-cell proliferation. We showed in this report that HBZ interacted with Smad2/3, and enhanced transforming growth factor-β (TGF-β)/Smad transcriptional responses in a p300-dependent manner. The N-terminal LXXLL motif of HBZ was responsible for HBZ-mediated TGF-β signaling activation. In a serial immunoprecipitation assay, HBZ, Smad3, and p300 formed a ternary complex, and the association between Smad3 and p300 was markedly enhanced in the presence of HBZ. In addition, HBZ could overcome the repression of the TGF-β response by Tax. Finally, HBZ expression resulted in enhanced transcription of Pdgfb, Sox4, Ctgf, Foxp3, Runx1, and Tsc22d1 genes and suppression of the Id2 gene; such effects were similar to those by TGF-β. In particular, HBZ induced Foxp3 expression in naive T cells through Smad3-dependent TGF-β signaling. Our results suggest that HBZ, by enhancing TGF-β signaling and Foxp3 expression, enables HTLV-1 to convert infected T cells into regulatory T cells, which is thought to be a critical strategy for virus persistence.

Topics: Animals; Basic-Leucine Zipper Transcription Factors; Cell Line; Cell Line, Tumor; E1A-Associated p300 Protein; Forkhead Transcription Factors; Gene Expression Regulation, Leukemic; Gene Expression Regulation, Viral; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Mice; Mice, Inbred C57BL; Protein Structure, Tertiary; Retroviridae Proteins; Signal Transduction; Smad Proteins, Receptor-Regulated; Transcription Factor AP-1; Transforming Growth Factor beta; Viral Proteins

Topics: Forkhead Transcription Factors; HTLV-I Infections; Humans; Immunophenotyping; Lymphoma, T-Cell, Cutaneous; Skin Neoplasms; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Human T lymphotrophic virus type-I (HTLV-I), a human retrovirus, infects CD4(+) lymphocytes and is thought to modify their function and a possible association with pulmonary diseases has also been suggested. However, little is known about the influence of HTLV-I on diffuse pan-bronchiolitis (DPB), a chronic inflammatory lung disease with infiltration of lymphocytes and hyperplasia of the bronchus-associated lymphoid tissue. In this study, 35 DPB patients with and without HTLV-I infection were examined. HTLV-I positive DPB patients were likely to have a larger affected area with lower FEV(1). The CD3(+)/CD25(+) lymphocyte percentage was significantly higher in the BALF of HTLV-I positive patients than in negative patients. MIP-1 alpha, IP-10 and levels in BALF were also significantly higher in HTLV-I positive patients than in negative patients. The levels of MCP-1 and IL-8 were not significantly different. In HTLV-I positive patients, the MIP-1 alpha and IP-10 levels showed a significant positive correlation with the percentage of CD3(+)/CD25 lymphocytes. BALF cells of all HTLV-I positive DPB patients showed expression of p40(tax) mRNA. We suggest that HTLV-I infection may modify DPB pathogenesis via activation of T cells. We also found that the frequency of ATL development in HTLV-I positive DPB patients was significantly higher than in all HTLV-I positive patients (OR = 8.22, 95% CI = 2.61-25.9, P < 0.01). The levels of TGF-beta in patients who developed ATL were significantly lower than in patients who did not develop ATL. Sensitivity and specificity were 80% and 85.7%, respectively (cut-off = 20 pg/ml). We also propose that these features should be taken into consideration in the treatment of DPB in HTLV-I infected individuals.

Topics: Adult; Aged; Bronchiolitis; Bronchoalveolar Lavage Fluid; CD4-Positive T-Lymphocytes; Chemokine CCL2; Chemokine CCL4; Chemokine CXCL10; Chi-Square Distribution; Chronic Disease; Female; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Interleukin-8; Lymphocyte Activation; Macrophage Inflammatory Proteins; Male; Middle Aged; Prevalence; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric; Transforming Growth Factor beta

Human T-cell leukemia virus type I (HTLV-I), the causative agent of adult T-cell leukemia/lymphoma, is transmitted vertically by breast milk and sexually by semen. The transforming growth factor-beta (TGF-beta), a pleiotropic cytokine that is abundant in breast milk and semen, facilitates replication of HTLV-I in lymphocytes derived from asymptomatic HTLV-I carriers and transmission to cord blood lymphocytes in vitro. Transient expression assays revealed that TGF-beta can transactivate HTLV-I long terminal repeat promoter. These results suggest that TGF-beta may play a role in replication and transmission of HTLV-I.

Topics: Cells, Cultured; Fetal Blood; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Leukocytes, Mononuclear; Milk, Human; Promoter Regions, Genetic; Semen; Terminal Repeat Sequences; Transcriptional Activation; Transforming Growth Factor beta; Virus Replication

Strongyloidiasis, a human intestinal infection caused by Strongyloides stercoralis (S. stercoralis), is difficult to cure with drugs. In particular, a decrease of the efficacy of treatment has been reported in patients dually infected with S. stercoralis and human T-cell leukaemia virus type I (HTLV-I), both of which are endemic in Okinawa, Japan. However, the factors influencing this resistance remain unclear. In the present study, patients infected with S. stercoralis, with or without HTLV-I infection, were treated with albendazole, followed up for one year and separated into two groups, cured and non-cured. The cure rate of S. stercoralis was lower in HTLV-I carriers (P < 0.05). Serum levels of S. stercoralis-specific IgA, IgE, IgG, IgG1 and IgG4 antibodies were estimated, and a decrease of IgE (P < 0.05) and an increase of IgG4 (P < 0.05) were observed in the non-cured group, especially in HTLV-I carriers. RT-PCR of cytokines using peripheral blood mononuclear cells revealed that S. stercoralis patients with HTLV-I showed a high frequency of expression of IFN-gamma and TGF-beta1, whereas those without HTLV-I showed no expression of these cytokines. IFN-gamma- and TGF-beta1-positive HTLV-I carriers showed a decrease of IgE (P < 0.05), an increase of IgG4 (P < 0.01) and a lower cure rate (P < 0.01) compared with those who were negative for both cytokines. These results suggest that persistent infection with HTLV-I affected S. stercoralis-specific immunity and reduced therapeutic efficacy.

Topics: Aged; Albendazole; Animals; Anthelmintics; Antibodies, Helminth; Feces; Female; Gene Expression Regulation; HTLV-I Infections; Humans; Immunocompromised Host; Immunoglobulin E; Immunoglobulin G; Interferon-gamma; Intestinal Diseases, Parasitic; Male; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Strongyloides stercoralis; Strongyloidiasis; Transforming Growth Factor beta; Treatment Failure

Human cytomegalovirus (HCMV) is one of the most frequent opportunistic agents causing severe illness in chronic human T cell leukemia-lymphoma virus type I (HTLV-I) infection. Our previous studies have shown that coinfection of macrophages with HCMV and HTLV-I significantly enhances HCMV replication, resulting in release of infectious HCMV from dually infected cells. We found that double infection of macrophages with HCMV and HTLV-I induced a rapid production of substantial amounts of interleukin-8 (IL-8) and transforming growth factor-beta1 (TGF-beta1). Results of transfection studies demonstrated that the tax gene product of HTLV-I was able to induce secretion of IL-8 and TGF-beta1. In addition to its cytokine-inducing effect, the Tax protein could interact with HCMV synergistically to result in production of much higher levels of IL-8 and TGF-beta1 than expected on the basis of their separate activities. Treatment of dually infected macrophage cultures with neutralizing antibodies to IL-8 and TGF-beta1 led to a nearly 1000-fold decrease in release of infectious HCMV from coinfected cells. Similar results were obtained when anti-IL-8 and anti-TGF-beta1 treatments were combined in macrophage cultures transfected with the tax gene before HCMV infection. Our results suggest that the stimulatory effect of HTLV-I Tax protein on HCMV replication in coinfected macrophages is largely mediated by high levels of IL-8 and TGF-beta1 production.

Topics: Antibodies, Monoclonal; Cell Line; Cytomegalovirus Infections; Gene Products, tax; HTLV-I Infections; Humans; Interleukin-8; Macrophages; Transforming Growth Factor beta; Virus Replication