The transcriptome of HTLV-1-infected primary cells following reactivation reveals changes to host gene expression central to the proviral life cycle
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ABSTRACT:
PROVIDER: PRJNA981458 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24875538_1.fastq.gz | Fastqsanger.gz | |||
| SRR24875538_2.fastq.gz | Fastqsanger.gz | |||
| SRR24875539_1.fastq.gz | Fastqsanger.gz | |||
| SRR24875539_2.fastq.gz | Fastqsanger.gz | |||
| SRR24875540_1.fastq.gz | Fastqsanger.gz |
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Project description: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 core to 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 them, 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.
2023-07-24 | GSE234450 | GEO
Project description: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.
| S-EPMC10431621 | biostudies-literature
Project description:Infection with the human T lymphotropic virus type 1 (HTLV-1) remains asymptomatic in the majority of carriers; however, some 5% develop a chronic inflammation of the central nervous system termed HTLV-1-associated myelopathy (HAM). It is not well understood how the virus triggers the onset of HAM after many years of clinical latency and importantly, what distinguishes hosts who develop the disease from those who remain asymptomatic. In this study we tested the hypothesis that patients with HAM can be distinguished from asymptomatic HTLV-1 carriers (ACs) and uninfected subjects by their whole blood transcriptional profiles. Here, we compare unstimulated whole blood gene expression profiles of 20 asymptomatic HTLV-1 carriers (ACs), 10 patients with HAM and 9 uninfected healthy control subjects to (1) identify a transcriptional signature associated with presence of HAM and (2) identify cell types and pathways abnormally regulated in HAM by canonical and modular pathway analysis. Patients attending the HTLV-1 clinic at St Mary’s hospital in London, UK were classified according to their clinical status as asymptomatic HTLV-1 carriers (ACs, n=20), patients with HTLV-1-associated meylopathy (HAM, n=10) or uninfected control subjects (n=9). HTLV-1 proviral load (PVL) can differ among individuals by more than 10-fold and is typically higher in patients with HAM than in ACs, with a 1% PVL cut off generally separating disease from asymptomatic carriage. Thus, ACs were subdivided into AC low PVL (<1% infected PBMCs) and AC high PVL (>1% infected PBMCs). Three ml of blood were drawn into a Tempus tube (Applied Biosystems, Foster City, CA, USA). Total RNA was extracted, globin mRNA depleted and following cRNA generation samples were analysed on HUmanHT12 v3 Illumina BeadChip arrays.
2012-01-01 | E-GEOD-29312 | biostudies-arrayexpress
Project description:Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles played by cellular genes in HTLV-1-infected CD4+ T cells await discovery. We combined microarray data and pathway analysis, and found that the ABL1 tyrosine kinase gene is a critical gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes. ABL1 is also part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML), and tyrosine kinase inhibitors (TKI), including imatinib, nilotinib, and dasatinib, are in safe clinical use for treating CML. To evaluate whether ABL1 is indeed critical for the pathogenesis of HAM/TSP, we investigated the effect of ABL1 inhibitors on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and DNA from dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKI. Treating the PBMCs with nilotinib or dasatinib produced significant reductions in the PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, a retrospective survey based on our clinical records found a rare case of HAM/TSP, where the patient also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is a significant gene for the survival of HTLV-1-infected cells and that TKI may be a potential therapeutic agent for HAM/TSP.
2020-05-26 | GSE132666 | GEO
Project description:Human T-cell leukemia virus type 1 (HTLV-1) is linked to the development of adult T-cell leukemia (ATL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax oncoprotein regulates viral gene expression and the NF-kB pathway to promote the survival of HTLV-1 infected T cells. In thsi study, we utilize a kinome-wide shRNA screen to identify the tyrosine kinase KDR/VEGFR2 as an essential survival factor of HTLV-1-transformed T cells. Inhibition of KDR induces apoptosis of Tax expressing HTLV-1-transformed cell lines and CD4+ T cells from HAM/TSP patients. Phosphoproteomics analysis of HTLV-1 transformed cells treated with a KDR inhibitor revealed inhibition of the phosphorylation of multiple receptors/cell surface proteins, ubiquitin conjugating systems, proteases, phosphatases, apoptotic regulatory factors, adhesion/extracellular matrix proteins and viral proteins. This work suggests that HTLV-1 Tax has hijacked KDR kinase activity to promote Tax stability and the proliferation and survival of HTLV-1 infected cells.
2024-06-14 | PXD051981 | Pride
Project description:HIV-1 eradication strategies require reactivation of all latent cells. Current methods lack effectiveness due to incomplete knowledge of proviral reactivation. We employed a single-molecule RNA-FISH (smRNA-FISH) analysis and found that proviral reactivation is highly variable, stochastic, and occurs in bursts and waves, with different kinetics in response to diverse LRAs. Approximately 1-5% of latent cells displayed stochastic reactivation even without stimulation. Through single-cell RNA-seq analysis, we identified NR4A3 and cMYC as extrinsic factors selectively associated with HIV-1 reactivation. Concomitant with HIV-1 reactivation cMYC was downregulated and NR4A3 was upregulated in both latent cell lines and primary CD4+ T-cells from aviremic patients. By inhibiting cMYC using SN-38, an active metabolite of irinotecan, we induced NR4A3 and HIV-1 expression. Our results suggest that inherent stochasticity in proviral reactivation contributes to cell-to-cell variability, which could potentially be modulated by drugs targeting cMYC and NR4A3.
2024-05-24 | GSE241207 | GEO
Project description:We used microarrays to compare the global programme of gene expression in HTLV-positive, ATL-derived and HTLV-positive in vitro-transformed cell lines with that of uninfected primary CD4 T cells.
2009-08-20 | GSE17718 | GEO
Project description:HTLV-1 preferentially infects CD4+ T cells and these cells play a central role in HTLV-1 infection. In this study, we investigated the global gene expression profile of circulating CD4+ T cells from distinct clinical status of HTLV-1-infected individuals in regard to Tax expression levels. CD4+ T cells were isolated from asymptomatic HTLV-1 carrier (HAC) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, in order to identify genes involved in the HAM/TSP development. Hierarchical clustering analysis showed that healthy controls (CT) and HTLV-1-infected samples clustered separately. We also observed that HAC and HAM/TSP groups clustered separately regardless Tax expression. The gene expression profile of CD4+ T cells was compared among CT, HAC and HAM/TSP groups. The IL-27, PXN, CXCR4, GZMA, PRF1 and Foxp3 genes were differentially expressed between HAC and HAM/TSP groups and the frequency of CD4+Foxp3+ regulatory T cells (Treg) were higher in HTLV-1-infected individuals. These findings suggest that CD4+ T cells activity is distinct between HAC and HAM/TSP groups as expected.
2013-06-01 | GSE38537 | GEO
Project description:We performed immunoprofiling of HTLV-1 Tax301-309 (SFHSLHLLF) specific CD8+ T cells in PB of HAM patients associated with T cell activation by single cell RNA sequencing (scRNA-seq).
2022-08-12 | GSE210786 | GEO
Project description:HTLV-1 preferentially infects CD4+ T cells and these cells play a central role in HTLV-1 infection. In this study, we investigated the global gene expression profile of circulating CD4+ T cells from distinct clinical status of HTLV-1-infected individuals in regard to Tax expression levels. CD4+ T cells were isolated from asymptomatic HTLV-1 carrier (HAC) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, in order to identify genes involved in the HAM/TSP development. Hierarchical clustering analysis showed that healthy controls (CT) and HTLV-1-infected samples clustered separately. We also observed that HAC and HAM/TSP groups clustered separately regardless Tax expression. The gene expression profile of CD4+ T cells was compared among CT, HAC and HAM/TSP groups. The IL-27, PXN, CXCR4, GZMA, PRF1 and Foxp3 genes were differentially expressed between HAC and HAM/TSP groups and the frequency of CD4+Foxp3+ regulatory T cells (Treg) were higher in HTLV-1-infected individuals. These findings suggest that CD4+ T cells activity is distinct between HAC and HAM/TSP groups as expected. In order to study the transcriptional changes in CD4 T cell from HTLV-1-infected individuals, immunomagnetically purified CD4+ T-cells from the peripheral blood of 4 asymptomatic HTLV-1 carrier individuals (HAC) and 4 individuals with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), as well as from 4 healthy controls (CT) were isolated and processed the microarray assay according Agilent's protocol. The differential expressed genes, molecular characterization and networks analysis were evaluated using robust bioinformatic tools, then the real time PCR was done to validate the genes.
2013-06-01 | E-GEOD-38537 | biostudies-arrayexpress