In vivo antagonistic role of the Human T-Cell Leukemia Virus Type 1 regulatory proteins Tax and HBZ

Akkouche, Abdou; Moodad, Sara; Hleihel, Rita; Skayneh, Hala; Chambeyron, Séverine; Hajj, Hiba El; Bazarbachi, Ali

doi:10.1371/journal.ppat.1009219

Cited by 17 publications

(17 citation statements)

References 72 publications

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“…Subsequently, for more than 35 years, virtually all efforts were directed towards the study of the viral transactivator protein, Tax, which was found to immortalize human lymphocytes in vitro and to transform them in vivo in transgenic animal models. Numerous studies have demonstrated that Tax activates CREB, NF-κB, and SRF signaling pathways [46], and causes numerous effects on host cell proteins involved in cell cycle regulation, cell division, tumor suppression, and DNA repair [47][48][49][50][51][52]. However, as we shall see below, Tax was not the sole actor on this stage.…”

Section: Discovery Of the First Human Retrovirus: Htlv-1 Birth Of Human Retrovirologymentioning

confidence: 97%

Retroviral Antisense Transcripts and Genes: 33 Years after First Predicted, a Silent Retroviral Revolution?

Miller

Zimmer

Moutot

et al. 2021

Viruses

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Paradigm shifts throughout the history of microbiology have typically been ignored, or met with skepticism and resistance, by the scientific community. This has been especially true in the field of virology, where the discovery of a “contagium vivum fluidum”, or infectious fluid remaining after excluding bacteria by filtration, was initially ignored because it did not coincide with the established view of microorganisms. Subsequent studies on such infectious agents, eventually termed “viruses”, were met with skepticism. However, after an abundance of proof accumulated, viruses were eventually acknowledged as defined microbiological entities. Next, the proposed role of viruses in oncogenesis in animals was disputed, as was the unique mechanism of genome replication by reverse transcription of RNA by the retroviruses. This same pattern of skepticism holds true for the prediction of the existence of retroviral “antisense” transcripts and genes. From the time of their discovery, it was thought that retroviruses encoded proteins on only one strand of proviral DNA. However, in 1988, it was predicted that human immunodeficiency virus type 1 (HIV-1), and other retroviruses, express an antisense protein encoded on the DNA strand opposite that encoding the known viral proteins. Confirmation came quickly with the characterization of the antisense protein, HBZ, of the human T-cell leukemia virus type 1 (HTLV-1), and the finding that both the protein and its antisense mRNA transcript play key roles in viral replication and pathogenesis. However, acceptance of the existence, and potential importance, of a corresponding antisense transcript and protein (ASP) in HIV-1 infection and pathogenesis has lagged, despite gradually accumulating theoretical and experimental evidence. The most striking theoretical evidence is the finding that asp is highly conserved in group M viruses and correlates exclusively with subtypes, or clades, responsible for the AIDS pandemic. This review outlines the history of the major shifts in thought pertaining to the nature and characteristics of viruses, and in particular retroviruses, and details the development of the hypothesis that retroviral antisense transcripts and genes exist. We conclude that there is a need to accelerate studies on ASP, and its transcript(s), with the view that both may be important, and overlooked, targets in anti-HIV therapeutic and vaccine strategies.

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Section: Discovery Of the First Human Retrovirus: Htlv-1 Birth Of Human Retrovirologymentioning

confidence: 97%

Retroviral Antisense Transcripts and Genes: 33 Years after First Predicted, a Silent Retroviral Revolution?

Miller

Zimmer

Moutot

et al. 2021

Viruses

View full text Add to dashboard Cite

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“…Among all described regulatory proteins, Tax and HBZ proteins were lengthily studied and are tightly allied to HTLV-1 pathogenesis (38)(39)(40)(41). While Tax is encoded by a sense mRNA, and upregulates various host genes promoting cell activation and proliferation [reviewed in (42-45)], HBZ is encoded by the minus strand of the pX region, and plays several roles, mostly counteracting Tax-induced cellular phenomena (Table 1) (see sections below) (35,47,53,64).…”

Section: Htlv-1 Encoded Proteins With Emphasis On Tax and Hbzmentioning

confidence: 99%

Interplay between innate immunity and the viral oncoproteins Tax and HBZ in the pathogenesis and therapeutic response of HTLV-1 associated adult T cell leukemia

Hajj

Bazarbachi

2022

Front. Immunol.

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The Human T-cell Leukemia virus type 1 (HTLV-1) causes an array of pathologies, the most aggressive of which is adult T-cell leukemia (ATL), a fatal blood malignancy with dismal prognosis. The progression of these diseases is partly ascribed to the failure of the immune system in controlling the spread of virally infected cells. HTLV-1 infected subjects, whether asymptomatic carriers or symptomatic patients are prone to opportunistic infections. An increasing body of literature emphasizes the interplay between HTLV-1, its associated pathologies, and the pivotal role of the host innate and adoptive immune system, in shaping the progression of HTLV-1 associated diseases and their response to therapy. In this review, we will describe the modalities adopted by the malignant ATL cells to subvert the host innate immune response with emphasis on the role of the two viral oncoproteins Tax and HBZ in this process. We will also provide a comprehensive overview on the function of innate immunity in the therapeutic response to chemotherapy, anti-viral or targeted therapies in the pre-clinical and clinical settings.

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“…Not surprisingly, the induction of this eye phenotype is primarily dependent on the Drosophila homolog of IKKγ/NEMO. Conversely, an Hbz transgenic Drosophila model neither induces transformation nor NF-κB activation in vivo [ 129 ]. Instead, Hbz overexpression prevents Tax-mediated NF-κB activation and rescues the Tax-induced transformation phenotype.…”

Section: In Vitro and In Vivo Models Usef...mentioning

confidence: 99%

Regulation of HTLV-1 transformation

Ernzen

Panfil

2022

Bioscience Reports

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Human T-cell leukemia virus type 1 (HTLV-1) is the only identified oncogenic human retrovirus. HTLV-1 infects approximately 5-10 million people worldwide and is the infectious cause of adult T-cell leukemia/lymphoma (ATL) and several chronic inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), dermatitis, and uveitis. Unlike other oncogenic retroviruses, HTLV-1 does not capture a cellular proto-oncogene or induce proviral insertional mutagenesis. HTLV-1 is a trans-activating retrovirus and encodes accessory proteins that induce cellular transformation over an extended period of time, upwards of several years to decades. Inarguably the most important viral accessory protein involved in transformation is Tax. Tax is a multifunctional protein that regulates several different pathways and cellular processes. This single viral protein is able to modulate viral gene expression, activate NF-kB signaling pathways, deregulate the cell cycle, disrupt apoptosis, and induce genomic instability. The summation of these processes results in cellular transformation and viral-mediated oncogenesis. Interestingly, HTLV-1 also encodes a protein called Hbz from the antisense strand of the proviral genome that counters many Tax functions in the infected cell, such as Tax-mediated viral transcription and NF-kB activation. However, Hbz also promotes cellular proliferation, inhibits apoptosis, and disrupts genomic integrity. In addition to viral proteins, there are other cellular factors such as MEF-2, Nox5α, and PDLIM2 which have been shown to be critical for HTLV-1-mediated T-cell transformation. This review will highlight the important viral and cellular factors involved in HTLV-1 transformation and the available in vitro and in vivo tools used to study this complex process.

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In vivo antagonistic role of the Human T-Cell Leukemia Virus Type 1 regulatory proteins Tax and HBZ

Cited by 17 publications

References 72 publications

Retroviral Antisense Transcripts and Genes: 33 Years after First Predicted, a Silent Retroviral Revolution?

Retroviral Antisense Transcripts and Genes: 33 Years after First Predicted, a Silent Retroviral Revolution?

Interplay between innate immunity and the viral oncoproteins Tax and HBZ in the pathogenesis and therapeutic response of HTLV-1 associated adult T cell leukemia

Regulation of HTLV-1 transformation

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