Post-transcriptional Regulation of HTLV Gene Expression: Rex to the Rescue

D’Agostino, Donna M.; Cavallari, Ilaria; Ciminale, Vincenzo

doi:10.3389/fmicb.2019.01958

Cited by 9 publications

(4 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Second, sequestration of the transcription co-factors CBP/p300 by HBZ protein [35]. Third, a progressive reduction in Tax translation caused by the accumulation of Rex protein [36]. Recent evidence suggests that transcription factors form phase-separated droplets where transcriptional bursts occur, and intrinsically disordered domains of transcription factors are particularly responsible for forming droplets [37, 38].…”

Section: Discussionmentioning

confidence: 99%

Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

et al. 2019

View full text Add to dashboard Cite

The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given time in each cell. However, cellular stress responses trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Using single-molecule RNA FISH, we measured the kinetics of the HTLV-1 transcriptional reactivation in peripheral blood mononuclear cells (PBMCs) isolated from HTLV-1+ individuals. The abundance of the HTLV-1 sense and antisense transcripts was quantified hourly during incubation of the HTLV-1-infected PBMCs ex vivo. We found that, in each cell, the sense-strand transcription occurs in two distinct phases: the initial low-rate transcription is followed by a phase of rapid transcription. The onset of transcription peaked between 1 and 3 hours after the start of in vitro incubation. The variance in the transcription intensity was similar in polyclonal HTLV-1+ PBMCs (with tens of thousands of distinct provirus insertion sites), and in samples with a single dominant HTLV-1+ clone. A stochastic simulation model was developed to estimate the parameters of HTLV-1 proviral transcription kinetics. In PBMCs from a leukemic subject with one dominant T-cell clone, the model indicated that the average duration of HTLV-1 sense-strand activation by Tax (i.e. the rapid transcription) was less than one hour. HTLV-1 antisense transcription was stable during reactivation of the sense-strand. The antisense transcript HBZ was produced at an average rate of ~0.1 molecules per hour per HTLV-1+ cell; however, between 20% and 70% of HTLV-1-infected cells were HBZ-negative at a given time, the percentage depending on the individual subject. HTLV-1-infected cells are exposed to a range of stresses when they are drawn from the host, which initiate the viral reactivation. We conclude that whereas antisense-strand transcription is stable throughout the stress response, the HTLV-1 sense-strand reactivation is highly heterogeneous and occurs in short, self-terminating bursts.

show abstract

Section: Discussionmentioning

confidence: 99%

Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The HTLV-1 regulatory genes Tax, Rex, p21, p12, p13 and p30 are all encoded by various open reading frames (ORFs) in the pX region located in the 3' end of the genome [43][44][45]. The accessory genes p12, p13 and p30 play significant roles in establishing and maintaining viral persistence, whereas Rex regulates post-transcriptional viral gene expression and increases the stability of viral RNA for the latency phase of the viral life cycle [46][47][48][49]. The HTLV-1 basic leucine zipper factor (HBZ) regulatory protein is transcribed in an antisense manner directed by the 3' LTR and is consistently expressed in ATLL [50,51].…”

Section: Htlv-1 Genomic Structure and Modes Of Entrymentioning

confidence: 99%

Mechanisms of Oncogenesis by HTLV-1 Tax

Mohanty

Harhaj

2020

Pathogens

View full text Add to dashboard Cite

The human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), a neoplasm of CD4+CD25+ T cells that occurs in 2–5% of infected individuals after decades of asymptomatic latent infection. Multiple HTLV-1-encoded regulatory proteins, including Tax and HTLV-1 basic leucine zipper factor (HBZ), play key roles in viral persistence and latency. The HTLV-1 Tax oncoprotein interacts with a plethora of host cellular proteins to regulate viral gene expression and also promote the aberrant activation of signaling pathways such as NF-κB to drive clonal proliferation and survival of T cells bearing the HTLV-1 provirus. Tax undergoes various post-translational modifications such as phosphorylation and ubiquitination that regulate its function and subcellular localization. Tax shuttles in different subcellular compartments for the activation of anti-apoptotic genes and deregulates the cell cycle with the induction of DNA damage for the accumulation of genomic instability that can result in cellular immortalization and malignant transformation. However, Tax is highly immunogenic and therefore HTLV-1 has evolved numerous strategies to tightly regulate Tax expression while maintaining the pool of anti-apoptotic genes through HBZ. In this review, we summarize the key findings on the oncogenic mechanisms used by Tax that set the stage for the development of ATLL, and the strategies used by HTLV-1 to tightly regulate Tax expression for immune evasion and viral persistence.

show abstract

“…HTLV-1 codes for the regulatory/accessory proteins Tax, Rex, p30, p13, p12, and HBZ in addition to the Gag, Env and Pol genes common to all retroviruses [reviewed by ( 6 , 7 )]. Tax and Rex are essential for productive viral infection, with Tax driving transcription of the plus-strand genome [reviewed by ( 8 )] and Rex functioning as an RNA escort that facilitates exit of plus-strand viral transcripts from the nucleus [reviewed by ( 9 )].…”

Section: Introductionmentioning

confidence: 99%

MiR-150 in HTLV-1 infection and T-cell transformation

et al. 2022

Self Cite

View full text Add to dashboard Cite

Human T-cell leukemia virus-1 (HTLV-1) is a retrovirus that persistently infects CD4+ T-cells, and is the causative agent of adult T-cell leukemia/lymphoma (ATLL), tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) and several inflammatory diseases. T-cell transformation by HTLV-1 is driven by multiple interactions between viral regulatory proteins and host cell pathways that govern cell proliferation and survival. Studies performed over the last decade have revealed alterations in the expression of many microRNAs in HTLV-1-infected cells and ATLL cells, and have identified several microRNA targets with roles in the viral life cycle and host cell turnover. This review centers on miR-150-5p, a microRNA whose expression is temporally regulated during lymphocyte development and altered in several hematological malignancies. The levels of miR-150-5p are reduced in many HTLV-1-transformed- and ATLL-derived cell lines. Experiments in these cell lines showed that downregulation of miR-150-5p results in activation of the transcription factor STAT1, which is a direct target of the miRNA. However, data on miR-150-5p levels in freshly isolated ATLL samples are suggestive of its upregulation compared to controls. These apparently puzzling findings highlight the need for more in-depth studies of the role of miR-150-5p in HTLV-1 infection and pathogenesis based on knowledge of miR-150-5p-target mRNA interactions and mechanisms regulating its function in normal leukocytes and hematologic neoplasms.

show abstract

Post-transcriptional Regulation of HTLV Gene Expression: Rex to the Rescue

Cited by 9 publications

References 64 publications

Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

Mechanisms of Oncogenesis by HTLV-1 Tax

MiR-150 in HTLV-1 infection and T-cell transformation

Contact Info

Product

Resources

About