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Journal of Inorganic Biochemistry Aug 2023Chalcone and thiosemicarbazone have attracted attention due to their easy synthetic procedure and high success in the development of antiviral and antitumor, however,...
Chalcone and thiosemicarbazone have attracted attention due to their easy synthetic procedure and high success in the development of antiviral and antitumor, however, there are few biological data on the evaluation of chalcone-thiosemicarbazone hybrids and their complexation with metal ions. In this sense, the present work reports the synthesis and characterization of the hybrid (Z)-2-((E)-3-(4-chlorophenyl)-1-phenylallylidene)hydrazine-1-carbothioamide (CTCl) and its Zn(II)-complex (CTCl-Zn). The compounds were cell-based evaluated in terms of cytotoxicity against human T-cell lymphotropic virus type 1 (HTLV-1) infected leukemia cells (MT-2) and the experimental data were correlated with molecular docking calculations. The ligand and Zn(II)-complex were easily synthesized with a good yield - 57% and 79%, respectively. The dynamic of E/Z isomers with respect to the imine bond configuration of CTCl was evidenced by H NMR experiments in DMSO‑d, while the X-ray diffraction of CTCl-Zn showed that Zn(II) ion is tetracoordinated to two ligands in a bidentate mode and the metal ion lies on an intermediate geometry between the see-saw and trigonal pyramid. The ligand and complex exhibited low toxicity and the Zn(II)-complex is more cytotoxic than the ligand, with the corresponding IC value of 30.01 and 47.06 μM. Both compounds had a pro-apoptotic effect without the release of reactive oxygen species (ROS) and they can interact with DNA via minor grooves driven by van der Waals forces.
Topics: Humans; Thiosemicarbazones; Ligands; Human T-lymphotropic virus 1; Chalcones; Molecular Docking Simulation; Chalcone; Human T-lymphotropic virus 2; Zinc; Antineoplastic Agents
PubMed: 37148641
DOI: 10.1016/j.jinorgbio.2023.112239 -
Bioorganic & Medicinal Chemistry Aug 2023Infection with the retrovirus human T-cell leukemia virus type 1 (HTLV-1) sometimes causes diseases that are difficult to cure. To find anti-HTLV-1 natural compounds, we...
Infection with the retrovirus human T-cell leukemia virus type 1 (HTLV-1) sometimes causes diseases that are difficult to cure. To find anti-HTLV-1 natural compounds, we opted to screen using the HTLV-1-infected T-cell line, MT-2. Based on our results, an extract of the pulp/seeds of Akebia quinata Decaisne fruit killed MT-2 cells but did not affect the Jurkat cell line that was not infected with virus. To determine the active ingredients, seven saponins with one-six sugar moieties were isolated from A. quinata seeds, and their activities against the two cell lines were examined. Both cell lines were killed in a similar manner by Akebia saponins A and B. Further, Akebia saponins D, E, P and G did not exhibit cytotoxicity. Akebia saponin C had a similar activity to the extract found in the screening. This compound was found to enhance Gag aggregation, induce the abnormal cleavage of Gag, suppress virion release, and preferentially kill HTLV-1 infected cells; however, their relationship remains elusive. Our findings may lead to the development of new therapies for infectious diseases based on the removal of whole-virus-infected cells.
Topics: Humans; Amidohydrolases; Cell Line; Human T-lymphotropic virus 1; Jurkat Cells; Plant Extracts; Saponins
PubMed: 37453188
DOI: 10.1016/j.bmc.2023.117408 -
Frontiers in Immunology 2024Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma. The HTLV-1 Tax constitutively activates nuclear factor-κB...
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma. The HTLV-1 Tax constitutively activates nuclear factor-κB (NF-κB) to promote the survival and transformation of HTLV-1-infected T cells. Despite extensive study of Tax, how Tax interacts with host factors to regulate NF-κB activation and HTLV-1-driven cell proliferation is not entirely clear. Here, we showed that overexpression of Poly (rC)-binding protein 1 (PCBP1) promoted Tax-mediated IκB kinase (IKK)-NF-κB signaling activation, whereas knockdown of PCBP1 attenuated Tax-dependent IKK-NF-κB activation. However, Tax activation of HTLV-1 long terminal repeat was unaffected by PCBP1. Furthermore, depletion of PCBP1 led to apoptosis and reduced proliferation of HTLV-1-transformed cells. Mechanistically, PCBP1 interacted and co-localized with Tax in the cytoplasm, and PCBP1 KH3 domain was indispensable for the interaction between PCBP1 and Tax. Moreover, PCBP1 facilitated the assembly of Tax/IKK complex. Collectively, our results demonstrated that PCBP1 may exert an essential effect in Tax/IKK complex combination and subsequent NF-κB activation, which provides a novel insight into the pathogenetic mechanisms of HTLV-1.
Topics: Humans; Gene Products, tax; NF-kappa B; Human T-lymphotropic virus 1; RNA-Binding Proteins; DNA-Binding Proteins; Heterogeneous-Nuclear Ribonucleoproteins; Signal Transduction; HEK293 Cells; Protein Binding; Cell Proliferation; HTLV-I Infections; Apoptosis; I-kappa B Kinase; Host-Pathogen Interactions
PubMed: 38690287
DOI: 10.3389/fimmu.2024.1375168 -
Journal of Veterinary Research Mar 2024Bovine leukaemia virus (BLV) is a Deltaretrovirus responsible for enzootic bovine leukosis, the most common neoplastic disease of cattle. It deregulates the immune...
INTRODUCTION
Bovine leukaemia virus (BLV) is a Deltaretrovirus responsible for enzootic bovine leukosis, the most common neoplastic disease of cattle. It deregulates the immune system, favouring secondary infections and changes in the blood and lymphatic tissues. Blood homeostasis depends on functional haematopoietic stem cells (HSCs). Bone marrow is populated by these cells, which express CD34 and CD35 surface antigens and produce and release cytokines involved in the maintenance of haematopoiesis. The aim of the study was determination of the profile of cytokine production by CD34 stem cells of cattle naturally infected with BLV.
MATERIAL AND METHODS
The HSCs were generated from the blood and lymphoid organs of cows infected with BLV and healthy control cows with immunomagnetic separation and anti-CD34 monoclonal antibodies. Isolated CD34 cells were cultivated for two weeks with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor. The levels of IL-6, IL-10, IL-12p40, IL-12p70, interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α) were determined in culture fluid by flow cytometry.
RESULTS
The expression of IL-6, IL-12p70 and TNF-α in blood HSCs was higher in BLV cows than in the control animals. In bone marrow HSCs of infected cows, IL-12, TNF-α and IFN-γ were more concentrated, but in these cows' spleen HSCs only expression of IL-10 was elevated. In HSCs isolated from the lymph nodes of leukaemic cows, only TNF-α secretion was lower than in control cows, the other cytokines being more potently secreted.
CONCLUSION
Infection with BLV caused statistically significant differences in cytokine expression by HSC CD34 cells.
PubMed: 38525233
DOI: 10.2478/jvetres-2024-0012 -
Pharmaceuticals (Basel, Switzerland) Jun 2024With an estimated 10 million people infected, the deltaretrovirus human T-cell lymphotropic virus type 1 (HTLV-1) is the second most prevalent pathogenic retrovirus in...
With an estimated 10 million people infected, the deltaretrovirus human T-cell lymphotropic virus type 1 (HTLV-1) is the second most prevalent pathogenic retrovirus in humans after HIV-1. Like HIV-1, HTLV-1 overwhelmingly persists in a host via a reservoir of latently infected CD4 T cells. Although most patients are asymptomatic, HTLV-1-associated pathologies are often debilitating and include adult T-cell leukaemia/lymphoma (ATLL), which presents in mature adulthood and is associated with poor prognosis with short overall survival despite treatment. Curiously, the strongest indicator for the development of ATLL is the acquisition of HTLV-1 through breastfeeding. There are no therapeutic or preventative regimens for HTLV-1. However, antiretrovirals (ARVs), which target the essential retrovirus enzymes, have been developed for and transformed HIV therapy. As the architectures of retroviral enzyme active sites are highly conserved, some HIV-specific compounds are active against HTLV-1. Here, we expand on our work, which showed that integrase strand transfer inhibitors (INSTIs) and some nucleoside reverse transcriptase inhibitors (NRTIs) block HTLV-1 transmission in cell culture. Specifically, we find that dolutegravir, the INSTI currently recommended as the basis of all new combination antiretroviral therapy prescriptions, and the latest prodrug formula of the NRTI tenofovir, tenofovir alafenamide, also potently inhibit HTLV-1 infection. Our results, if replicated in a clinical setting, could see transmission rates of HTLV-1 and future caseloads of HTLV-1-associated pathologies like ATLL dramatically cut via the simple repurposing of already widely available HIV pills in HTLV-1 endemic areas. Considering our findings with the old medical saying "it is better to prevent than cure", we highly recommend the inclusion of INSTIs and tenofovir prodrugs in upcoming HTLV-1 clinical trials as potential prophylactics.
PubMed: 38931397
DOI: 10.3390/ph17060730 -
Brazilian Journal of Microbiology :... Sep 2023The present study had the objective to describe the molecular prevalence and epidemiological aspects of the human T-lymphotropic virus 2 (HTLV-2) infection in the blood...
INTRODUCTION
The present study had the objective to describe the molecular prevalence and epidemiological aspects of the human T-lymphotropic virus 2 (HTLV-2) infection in the blood donor population of the Pará state.
METHODS
The present study is a descriptive, retrospective, and cross-sectional review of epidemiological, serological, and molecular data on inapt blood donors in the State Center for Hematology and Hemotherapy from January 2015 to December 2021. The data were digitalized to create a database using the Statistical Package for Social Sciences program. The prevalence of HTLV-2 was calculated based on the total number of donations during the study period. Descriptive frequency was used to analyze the qualitative data.
RESULTS
A total of 665,568 blood donations were made. Out of these, 1884 (0.2%) samples presented serological detection to HTLV and further were evaluated using molecular confirmatory tests. Out of these, 36 samples were positive for HTLV-2 using qPCR Taqman assay based on pol gene region (0.005%). The HTLV-2 was found to be more prevalent in women (63.9%); aged between 39 and 59 years (55.6%); residents of the metropolitan region of Belém (80.6%); with self-declared race as brown (80.6%); individuals who had completed high school (58.6%); and first-time donors (58.3%) CONCLUSION: The present study identified the presence of HTLV-2 (1 HTLV-2 case/20,000 donations; 0.005%) in the specific population of blood donors in Pará state. These findings can contribute to the existing literature on the subject both for specific population groups under study and for understanding the prevalence of HTLV-2 in the general population.
Topics: Humans; Female; Adult; Middle Aged; Human T-lymphotropic virus 2; Blood Donors; Human T-lymphotropic virus 1; HTLV-I Infections; Prevalence; Brazil; Cross-Sectional Studies; Retrospective Studies
PubMed: 37454039
DOI: 10.1007/s42770-023-01067-2 -
JCI Insight Jan 2024Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus with preferential CD4+ T cell tropism that causes a range of conditions spanning from asymptomatic infection...
Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus with preferential CD4+ T cell tropism that causes a range of conditions spanning from asymptomatic infection to adult T cell leukemia and HTLV-1-associated myelopathy (HAM), an inflammatory disease of the CNS. The mechanisms by which HTLV-1 induces HAM are poorly understood. By directly examining the ex vivo phenotype and function of T cells from asymptomatic carriers and patients with HAM, we show that patients with HAM have a higher frequency of CD4+CD8+ double-positive (DP) T cells, which are infected with HTLV-1 at higher rates than CD4+ T cells. Displaying both helper and cytotoxic phenotypes, these DP T cells are highly proinflammatory and contain high frequencies of HTLV-1-specific cells. Mechanistically, we demonstrate that DP T cells arise by direct HTLV-1 infection of CD4+ and CD8+ T cells. High levels of CD49d and CXCR3 expression suggest that DP T cells possess the ability to migrate to the CNS, and when cocultured with astrocytes, DP T cells induce proinflammatory astrocytes that express high levels of CXCL10, IFN-γ, and IL-6. These results demonstrate the potential of DP T cells to directly contribute to CNS pathology.
Topics: Humans; Astrocytes; Bone Marrow Diseases; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Human T-lymphotropic virus 1; Paraparesis, Tropical Spastic
PubMed: 38193535
DOI: 10.1172/jci.insight.173738 -
Multiple Sclerosis and Related Disorders Jul 2024The roles of endocannabinoids are described in immune modulation and neuroprotection. HTLV-1-associated myelopathy (HAM/TSP) is an inflammatory neurodegenerative...
BACKGROUND/AIM
The roles of endocannabinoids are described in immune modulation and neuroprotection. HTLV-1-associated myelopathy (HAM/TSP) is an inflammatory neurodegenerative disease. Therefore, in this study, the interactions of HTLV-1 regulatory factors and host cannabinoid receptors (CBRs) were evaluated in HAM/TSP.
METHODS
Nineteen HAM/TSPs, 22 asymptomatic carriers (ACs), and 18 healthy controls (HCs) were enrolled. RNA was extracted from PBMCs and then reverse-transcribed to cDNA. The gene expression of CB1R and CB2R, as well as HTLV-1 proviral load (PVL), Tax and HTLV-1 basic leucine zipper factor (HBZ) were assessed by RT-qPCR.
RESULTS
The mean expression of CB1R in ACs (8.51 ± 2.76) was significantly higher than HAMTSPs (1.593 ± 0.74, p = 0.05) and also HCs (0.10 ± 0.039, p = 0.001). The CB2R gene expression level in ACs (2.62±0.44) was significantly higher than HAM/TSPs (0.59 ± 0.15, p = 0.001) and HCs (1.00 ± 0.2, p = 0.006). Meanwhile there was a strong correlation between CB1R and CB2R gene expression levels in the HCs and HAM/TSPs (p = 0.001). HTLV-1-Tax expression in HAM/TSPs (386 ± 104) was higher than ACs (75 ± 32) and statistically significant (p = 0.003). While HTLV-1-HBZ was only expressed in three AC subjects and five HAM/TSPs, thus it cannot be analyzed.
CONCLUSION
The up-regulation of CB2R has immunomodulatory effects in inflammatory reactions. While CB1R as a neuroprotective agent may suppress inflammatory reactions in ACs, preventing HAM/TSP. It seems that, like multiple sclerosis (MS), cannabinoid medications are beneficial in HAM/TSP.
Topics: Humans; Male; Female; Receptor, Cannabinoid, CB1; Adult; Receptor, Cannabinoid, CB2; Paraparesis, Tropical Spastic; Middle Aged; Human T-lymphotropic virus 1; Gene Products, tax; Basic-Leucine Zipper Transcription Factors; Viral Load; Retroviridae Proteins
PubMed: 38704874
DOI: 10.1016/j.msard.2024.105659 -
Veterinary Immunology and... Feb 2024Bovines infected by bovine leukemia virus (BLV) are characterized by presenting low proviral load (LPL) or high proviral load (HPL). It is reported that animals with HPL...
Altered apoptosis and proliferation in milk cells and PBMc from BLV-infected bovines with different proviral loads: Possible role of the BCL-2 family proteins, TNF-alpha, and receptors.
Bovines infected by bovine leukemia virus (BLV) are characterized by presenting low proviral load (LPL) or high proviral load (HPL). It is reported that animals with HPL in peripheral blood mononuclear cells (PBMCs) present a decrease in apoptosis, an increase in viability and the proliferation rate, while animals that maintain an LPL have an intrinsic ability to control the infection, presenting an increased apoptosis rate of their PBMCs. However, there is little information on the effect of BLV on these mechanisms when the virus infects somatic milk cells (SC). This study investigates the mechanisms underlying apoptosis in milk and blood from BLV-infected animals with HPL and LPL. Relative levels of mRNA of tumor necrosis factor-α (TNF-α), TNF receptor 1 (TNF-RI), TNF receptor 2 (TNF-RII), anti-apoptotic B-cell lymphoma 2 protein (Bcl-2), and pro-apoptotic Bcl-2-like protein 4 (Bax) were measured in SC and PBMCs using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay. A significant decrease in the expression of TNF-α in SC from HPL animals vs non-infected bovines was observed, but the infection in SC with BLV did not show a modulation on the expression of TNF receptors. A significant increase in TNF-RI expression in PBMCs from HPL bovines compared to LPL bovines was observed. No significant differences in PBMCs between HPL and LPL compared to non-infected animals concerning TNF-α, TNF-RI, and TNF-RII expression were found. There was a significant increase of both Bcl-2 and Bax in SC from LPL compared to non-infected bovines, but the Bcl-2/Bax ratio showed an anti-apoptotic profile in LPL and HPL bovines compared to non-infected ones. Reduced mRNA expression levels of Bax were determined in the PBMCs from HPL compared to LPL subjects. In contrast, BLV-infected bovines did not differ significantly in the mRNA expression of Bax compared to non-infected bovines. Our data suggest that the increased mRNA expression of Bax corresponds to the late lactation state of bovine evaluated and the exacerbated increase of mRNA expression of Bcl-2 may be one of the mechanisms for the negative apoptosis regulation in the mammary gland induced by BLV infection. These results provide new insights into the mechanism of mammary cell death in HPL and LPL BLV-infected bovine mammary gland cells during lactation.
Topics: Animals; Cattle; Female; Apoptosis; bcl-2-Associated X Protein; Cattle Diseases; Cell Proliferation; Enzootic Bovine Leukosis; Leukemia Virus, Bovine; Leukocytes, Mononuclear; Milk; Proviruses; Receptors, Tumor Necrosis Factor, Type II; RNA, Messenger; Tumor Necrosis Factor-alpha
PubMed: 38154260
DOI: 10.1016/j.vetimm.2023.110703 -
British Journal of Haematology Sep 2023
Topics: Humans; Human T-lymphotropic virus 1; Blood Donation; HTLV-I Infections; Human T-lymphotropic virus 2; Blood Donors; Prevalence; Mass Screening
PubMed: 37487701
DOI: 10.1111/bjh.18988