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International Journal of Molecular... Aug 2023HTLV-1 is an oncogenic human retrovirus and the etiologic agent of the highly aggressive ATL malignancy. Two viral genes, and , are individually linked to oncogenic...
HTLV-1 is an oncogenic human retrovirus and the etiologic agent of the highly aggressive ATL malignancy. Two viral genes, and , are individually linked to oncogenic transformation and play an important role in the pathogenic process. Consequently, regulation of HTLV-1 gene expression is a central feature in the viral lifecycle and directly contributes to its pathogenic potential. Herein, we identified the cellular transcription factor YBX1 as a binding partner for HBZ. We found YBX1 activated transcription and enhanced Tax-mediated transcription from the viral 5' LTR promoter. Interestingly, YBX1 also interacted with Tax. shRNA-mediated loss of YBX1 decreased transcript and protein abundance of both Tax and HBZ in HTLV-1-transformed T-cell lines, as well as Tax association with the 5' LTR. Conversely, YBX1 transcriptional activation of the 5' LTR promoter was increased in the absence of HBZ. YBX1 was found to be associated with both the 5' and 3' LTRs in HTLV-1-transformed and ATL-derived T-cell lines. Together, these data suggest that YBX1 positively influences transcription from both the 5' and 3' promoter elements. YBX1 is able to interact with Tax and help recruit Tax to the 5' LTR. However, through interactions with HBZ, YBX1 transcriptional activation of the 5' LTR is repressed.
Topics: Humans; Genes, Viral; Human T-lymphotropic virus 1; Promoter Regions, Genetic; RNA, Small Interfering; Terminal Repeat Sequences; Y-Box-Binding Protein 1
PubMed: 37685922
DOI: 10.3390/ijms241713119 -
Pathology, Research and Practice Mar 2024Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive form of cancer associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. The emerging... (Review)
Review
Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive form of cancer associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. The emerging field of stem cell therapies for ATLL is discussed, highlighting the potential of hematopoietic stem cell transplantation (HSCT) and genetically modified stem cells. HSCT aims to eradicate malignant T-cells and restore a functional immune system through the infusion of healthy donor stem cells. Genetically modified stem cells show promise in enhancing their ability to target and eliminate ATLL cells. The article presents insights from preclinical studies and limited clinical trials, emphasizing the need for further research to establish the safety, efficacy, and long-term outcomes of stem cell therapies for ATLL and challenges associated with these innovative approaches are also explored. Overall, stem cell therapies hold significant potential in revolutionizing ATLL treatment, and ongoing clinical trials aim to determine their benefits in larger patient populations.
Topics: Adult; Humans; Leukemia-Lymphoma, Adult T-Cell; Human T-lymphotropic virus 1; Hematopoietic Stem Cell Transplantation; Lymphoma
PubMed: 38340584
DOI: 10.1016/j.prp.2024.155172 -
Open Veterinary Journal Aug 2023Enzootic bovine leukosis (EBL) is a lymphoproliferative disorder caused by the bovine leukemia virus (BLV), a virus of the Retroviridae family. The infection is...
BACKGROUND
Enzootic bovine leukosis (EBL) is a lymphoproliferative disorder caused by the bovine leukemia virus (BLV), a virus of the Retroviridae family. The infection is distributed worldwide, and a high percentage of animals infected by the BLV are asymptomatic and act as carriers of the virus in many cattle populations.
AIM
To identify the risk factors associated with EBL in the municipalities of Boyacá and Cundinamarca (Colombia).
METHODS
A simple descriptive cross-sectional study with random sampling was conducted. A total of 1,140 blood samples were taken from cattle (females and males) from the municipalities of Chiquinquirá, Ubaté, and San Miguel de Sema of different breeds and age groups. The samples were processed using the commercial ELISA SERELISA® BLV Ab Mono Blocking kit (sensitivity 97%, specificity 98%). The data were processed with the statistical programs WinEpi and Epi Info® version 7.2.4.0, estimating the prevalence ratio, implementing the chi-square test ( ≤ 0.05) and logistic regression.
RESULTS
A true prevalence (TP) and apparent prevalence (AP) of 23.61% and 22.7% in Ubaté, 19.22% and 18.1% in Chiquinquirá, and 15.61% and 14.3% in San Miguel de Sema, respectively, were established. Bovines 2-4 years old were the most prevalent in Ubaté and Chiquinquirá (37.5% and 21.21%, respectively), while in San Miguel de Sema individuals >4 years had the highest percentage of antibodies (18.3%). The Holstein breed had a higher prevalence in Ubaté and San Miguel de Sema (26.02% and 19.67%), and crossbreeds were more BLV-seroprevalence in Chiquinquirá (20.20%). In Ubaté, re-use of needles was identified as a risk factor, contaminated blood in needles is considered one of the main routes of transmission. On the other hand, manual milking was identified as a risk factor in San Miguel de Sema.
CONCLUSION
The non-implementation of an individual needle per animal in Ubaté; the Holstein breed and manual milking in San Miguel de Sema were identified as risk factors for the presence of antibodies against the disease. EBL prevention and control plans should be established that focus on the implementation of management and sanitary practices based on herd biosecurity.
Topics: Animals; Cattle; Female; Male; Colombia; Cities; Cross-Sectional Studies; Enzootic Bovine Leukosis; Seroepidemiologic Studies; Risk Factors; Leukemia Virus, Bovine; Cattle Diseases
PubMed: 37701663
DOI: 10.5455/OVJ.2023.v13.i8.7 -
BMC Infectious Diseases Jan 2024Whether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown. (Observational Study)
Observational Study
BACKGROUND
Whether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown.
METHODS
To investigate humoral immunity after COVID-19 vaccination in HTLV-1 carriers, a multicenter, prospective observational cohort study was conducted at five institutions in southwestern Japan, an endemic area for HTLV-1. HTLV-1 carriers and HTLV-1-negative controls were enrolled for this study from January to December 2022. During this period, the third dose of the COVID-19 vaccine was actively administered. HTLV-1 carriers were enrolled during outpatient visits, while HTLV-1-negative controls included health care workers and patients treated by participating institutions for diabetes, hypertension, or dyslipidemia. The main outcome was the effect of HTLV-1 infection on the plasma anti-COVID-19 spike IgG (IgG-S) titers after the third dose, assessed by multivariate linear regression with other clinical factors.
RESULTS
We analyzed 181 cases (90 HTLV-1 carriers, 91 HTLV-1-negative controls) after receiving the third dose. HTLV-1 carriers were older (median age 67.0 vs. 45.0 years, p < 0.001) and more frequently had diabetes, hypertension, or dyslipidemia than did HTLV-1-negative controls (60.0% vs. 27.5%, p < 0.001). After the third dose, the IgG-S titers decreased over time in both carriers and controls. Multivariate linear regression in the entire cohort showed that time since the third dose, age, and HTLV-1 infection negatively influenced IgG-S titers. After adjusting for confounders such as age, or presence of diabetes, hypertension, or dyslipidemia between carriers and controls using the overlap weighting propensity score method, and performing weighted regression analysis in the entire cohort, both time since the third dose and HTLV-1 infection negatively influenced IgG-S titers.
CONCLUSIONS
The humoral immunity after the third vaccination dose is impaired in HTLV-1 carriers; thus, customized vaccination schedules may be necessary for them.
Topics: Humans; Aged; Human T-lymphotropic virus 1; COVID-19; COVID-19 Vaccines; Immunity, Humoral; Prospective Studies; HTLV-I Infections; Hypertension; Vaccination; Diabetes Mellitus; Dyslipidemias; Immunoglobulin G; Antibodies, Viral
PubMed: 38233756
DOI: 10.1186/s12879-024-09001-z -
PLoS Pathogens Jul 2023Infections by Human T cell Leukaemia Virus type 1 (HTLV-1) persist for the lifetime of the host by integrating into the genome of CD4+ T cells. Proviral gene expression...
Infections by Human T cell Leukaemia Virus type 1 (HTLV-1) persist for the lifetime of the host by integrating into the genome of CD4+ T cells. Proviral gene expression is essential for proviral survival and the maintenance of the proviral load, through the pro-proliferative changes it induces in infected cells. Despite their role in HTLV-1 infection and a persistent cytotoxic T lymphocyte response raised against the virus, proviral transcripts from the sense-strand are rarely detected in fresh cells extracted from the peripheral blood, and have recently been found to be expressed intermittently by a small subset of cells at a given time. Ex vivo culture of infected cells prompts synchronised proviral expression in infected cells from peripheral blood, allowing the study of factors involved in reactivation in primary cells. Here, we used bulk RNA-seq to examine the host transcriptome over six days in vitro, following proviral reactivation in primary peripheral CD4+ T cells isolated from subjects with non-malignant HTLV-1 infection. Infected cells displayed a conserved response to reactivation, characterised by discrete stages of gene expression, cell division and subsequently horizontal transmission of the virus. We observed widespread changes in Polycomb gene expression following reactivation, including an increase in PRC2 transcript levels and diverse changes in the expression of PRC1 components. We hypothesize that these transcriptional changes constitute a negative feedback loop that maintains proviral latency by re-deposition of H2AK119ub1 following the end of proviral expression. Using RNAi, we found that certain deubiquitinases, BAP1, USP14 and OTUD5 each promote proviral transcription. These data demonstrate the detailed trajectory of HTLV-1 proviral reactivation in primary HTLV-1-carrier lymphocytes and the impact on the host cell.
Topics: Humans; Human T-lymphotropic virus 1; Proviruses; HTLV-I Infections; Transcriptome; CD4-Positive T-Lymphocytes; Viral Load; Ubiquitin Thiolesterase
PubMed: 37523412
DOI: 10.1371/journal.ppat.1011494 -
Proceedings of the National Academy of... Aug 2023Retroviruses and their host have coevolved in a delicate balance between viral replication and survival of the infected cell. In this equilibrium, restriction factors...
Retroviruses and their host have coevolved in a delicate balance between viral replication and survival of the infected cell. In this equilibrium, restriction factors expressed by infected cells control different steps of retroviral replication such as entry, uncoating, nuclear import, expression, or budding. Here, we describe a mechanism of restriction against human T cell leukemia virus type 1 (HTLV-1) by the helicase-like transcription factor (HLTF). We show that RNA and protein levels of HLTF are reduced in primary T cells of HTLV-1-infected subjects, suggesting a clinical relevance. We further demonstrate that the viral oncogene Tax represses HLTF transcription via the Enhancer of zeste homolog 2 methyltransferase of the Polycomb repressive complex 2. The Tax protein also directly interacts with HLTF and induces its proteasomal degradation. RNA interference and gene transduction in HTLV-1-infected T cells derived from patients indicate that HLTF is a restriction factor. Restoring the normal levels of HLTF expression induces the dispersal of the Golgi apparatus and overproduction of secretory granules. By synergizing with Tax-mediated NF-κB activation, physiologically relevant levels of HLTF intensify the autophagic flux. Increased vesicular trafficking leads to an enlargement of the lysosomes and the production of large vacuoles containing viral particles. HLTF induction in HTLV-1-infected cells significantly increases the percentage of defective virions. In conclusion, HLTF-mediated activation of the autophagic flux blunts the infectious replication cycle of HTLV-1, revealing an original mode of viral restriction.
Topics: Humans; Human T-lymphotropic virus 1; Transcription Factors; Gene Products, tax; T-Lymphocytes; Leukemia, T-Cell; NF-kappa B; DNA-Binding Proteins
PubMed: 37487091
DOI: 10.1073/pnas.2216127120 -
The Lancet. Global Health Aug 2023
Topics: Female; Humans; Pregnancy; Human T-lymphotropic virus 1; Infectious Disease Transmission, Vertical; Breast Feeding; Pregnancy Complications, Infectious
PubMed: 37474224
DOI: 10.1016/S2214-109X(23)00268-1 -
Virus Research Dec 2023Adult T-cell leukemia/lymphoma (ATLL) is a poor prognosis malignancy of peripheral T-cells caused by human T-cell leukemia virus type 1 (HTLV-1). The low survival rates...
BACKGROUND
Adult T-cell leukemia/lymphoma (ATLL) is a poor prognosis malignancy of peripheral T-cells caused by human T-cell leukemia virus type 1 (HTLV-1). The low survival rates observed in the patients are the result of the lack of sufficient knowledge about the disease pathogenesis.
METHODS
In the present study, we first identified differentially expressed genes in ATLL patients and the cellular signaling pathways affected by them. Then, genes of these pathways were subjected to more comprehensive evaluations, including WGCNA and module validation studies on five external datasets. Finally, potential biomarkers were selected for qRT-PCR validation.
RESULTS
Thirteen signaling pathways, including Apoptosis, Human T-cell leukemia virus 1 infection, IL-17 signaling pathway, pathways in cancer, T cell receptor signaling pathway, Th1 and Th2 cell differentiation, and seven others were selected for deeper investigations. Results of our in-depth bioinformatics evaluations, highlighted pathways related to regulation of immune responses, T-cell receptor and activation, regulation of cell signaling receptors and messengers, Wnt signaling pathway, and apoptosis as key players in ATLL pathogenesis. MAPK3, PIK3CD, KRAS, NFKB1, TNF, PLCB3, PLCB2, PLCB1, MAPK11, JUN, ITPR1, ADCY1, GNAQ, ADCY3, ADCY4, CHEK1, CCND1, SOS2, BAX, FOS and GNA12 were identified as possible biomarkers. Upregulation of ADCY1 and ADCY3 genes was confirmed via qRT-PCR.
CONCLUSIONS
In this study, we performed a deep bioinformatic examination on a limited set of genes with high probabilities of involvement in the pathogenesis of ATLL. Our results highlighted signaling pathways and genes with potential key roles in disease formation and resistance against current treatment strategies. Further studies are required to test the possible benefits of highlighted genes as biomarkers and targets of treatment.
Topics: Adult; Humans; Leukemia-Lymphoma, Adult T-Cell; Human T-lymphotropic virus 1; Transcriptome; Receptors, Cell Surface; Lymphoma; Biomarkers
PubMed: 37832654
DOI: 10.1016/j.virusres.2023.199237 -
Cancer Science Jan 2024Human T-cell leukemia virus type 1 (HTLV-1) establishes chronic infection in humans and induces a T-cell malignancy called adult T-cell leukemia-lymphoma (ATL) and...
Human T-cell leukemia virus type 1 (HTLV-1) establishes chronic infection in humans and induces a T-cell malignancy called adult T-cell leukemia-lymphoma (ATL) and several inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Persistent HTLV-1 infection is established under the pressure of host immunity, and therefore the immune response against HTLV-1 is thought to reflect the status of the disease it causes. Indeed, it is known that cellular immunity against viral antigens is suppressed in ATL patients compared to HAM/TSP patients. In this study, we show that profiling the humoral immunity to several HTLV-1 antigens, such as Gag, Env, and Tax, and measuring proviral load are useful tools for classifying disease status and predicting disease development. Using targeted sequencing, we found that several carriers whom this profiling method predicted to be at high risk for developing ATL indeed harbored driver mutations of ATL. The clonality of HTLV-1-infected cells in those carriers was still polyclonal; it is consistent with an early stage of leukemogenesis. Furthermore, this study revealed significance of anti-Gag proteins to predict high risk group in HTLV-1 carriers. Consistent with this finding, anti-Gag cytotoxic T lymphocytes (CTLs) were increased in patients who received hematopoietic stem cell transplantation and achieved remission state, indicating the significance of anti-Gag CTLs for disease control. Our findings suggest that our strategy that combines anti-HTLV-1 antibodies and proviral load may be useful for prediction of the development of HTLV-1-associated diseases.
Topics: Adult; Humans; Human T-lymphotropic virus 1; Leukemia-Lymphoma, Adult T-Cell; Proviruses; Paraparesis, Tropical Spastic; Biomarkers; Viral Load
PubMed: 37950425
DOI: 10.1111/cas.15997 -
Skinmed 2023A 44-year-old woman presented to a plastic surgeon for liposuction of the abdomen, back, and flanks, a gluteal fat transfer, and a vertical pattern breast lift and small...
A 44-year-old woman presented to a plastic surgeon for liposuction of the abdomen, back, and flanks, a gluteal fat transfer, and a vertical pattern breast lift and small reduction. The patient had a medical history of significantly well-controlled hypertension for 4 years treated with hydrochlorothiazide and amlodipine. She had been pregnant four times and delivered six children with two sets of twins. She was allergic to latex and denied a history of smoking. Her physical examination was unremarkable and her body mass index (BMI) was 26.1. No skin lesions were evident (Figure 1). Her preoperative laboratory findings were within normal limits, with unremarkable electrocardiogram (EKG), chest x-ray, and mammogram. The patient underwent a successful surgical procedure, and the excised breast tissue and skin were sent to pathology for routine evaluation. Surgery removed 220 g of breast tissue from the left breast and 45 g was excised from the right one. The histopathology depicted atypical T-cells in the epidermis and superficial dermis of both left and right breasts. Physical examination failed to evidence lymph-adenopathy or masses. The patient denied weight loss, night sweats, or fever; however, due to her Caribbean heritage, adult T-cell leukemia/ lymphoma was considered and submitted for further histologic workup.
Topics: Adult; Child; Female; Humans; Human T-lymphotropic virus 1; Incidental Findings; Skin; Skin Diseases; HTLV-I Infections; Lipectomy
PubMed: 37771025
DOI: No ID Found