Human T-Cell Leukemia Virus Type 1 (HTLV-1) bZIP Factor Requires Cellular Transcription Factor JunD To Upregulate HTLV-1 Antisense Transcription from the 3′ Long Terminal Repeat

Gazon, Hélène; Lemasson, Isabelle; Polakowski, Nicholas; Césaire, Raymond; Matsuoka, Masao; Barbeau, Benoı̂t; Mesnard, Jean-Michel; Péloponèse, Jean-Marie

doi:10.1128/jvi.00661-12

Cited by 55 publications

(65 citation statements)

References 64 publications

(98 reference statements)

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“…Like HIV-1 antisense promoter, the HTLV-1 3′ LTR is a TATA-less promoter harboring many INR motifs, thus leading to a multitude of antisense transcription initiation sites [31, 34, 35]. The transcription of hbz relies heavily on three Sp1 sites in the U5 region of the proviral 3′ LTR [23, 31, 34, 36]. In luciferase assays, HTLV-1 antisense promoter activity is markedly reduced upon mutation of single or multiple Sp1 sites [34].…”

Section: Antisense Transcription Among Exogenous Retrovirusesmentioning

confidence: 99%

The sense behind retroviral anti-sense transcription

Manghera

Magnusson

Douville

2017

Virol J

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Retroviruses are known to rely extensively on the expression of viral proteins from the sense proviral genomic strand. Yet, the production of regulatory retroviral proteins from antisense-encoded viral genes is gaining research attention, due to their clinical significance. This report will discuss what is known about antisense transcription in Retroviridae, and provide new information about antisense transcriptional regulation through a comparison of Human Immunodeficiency Virus (HIV), Human T-cell Lymphotrophic Virus (HTLV-1) and endogenous retrovirus-K (ERVK) long terminal repeats (LTRs). We will attempt to demonstrate that the potential for antisense transcription is more widespread within retroviruses than has been previously appreciated, with this feature being the rule, rather than the exception.

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Section: Antisense Transcription Among Exogenous Retrovirusesmentioning

confidence: 99%

The sense behind retroviral anti-sense transcription

Manghera

Magnusson

Douville

2017

Virol J

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“…However, using the rabbit model of infection, HBZ was required for efficient HTLV-1 infection and persistence (27). These studies and others have provided evidence that HBZ is a secondary oncogene that plays a key role in cell proliferation (25,26,28,29) and cell survival (29,30). The antisense-strand protein of HTLV-2 (APH-2) has been detected in most HTLV-2-infected samples (31,32).…”

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confidence: 99%

Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis

Panfil

Dissinger

Howard

et al. 2016

J Virol

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Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that transform T cells in vitro but have distinct pathological outcomes in vivo. HTLV-1 encodes a protein from the antisense strand of its proviral genome, the HTLV-1 basic leucine zipper factor (HBZ), which inhibits Tax-1-mediated viral transcription and promotes cell proliferation, a high proviral load, and persistence in vivo. In adult T-cell leukemia/lymphoma (ATL) cell lines and patient T cells, hbz is often the only viral gene expressed. The antisense strand of the HTLV-2 proviral genome also encodes a protein termed APH-2. Like HBZ, APH-2 is able to inhibit Tax-2-mediated viral transcription and is detectable in most primary lymphocytes from HTLV-2-infected patients. However, unlike HBZ, the loss of APH-2 in vivo results in increased viral replication and proviral loads, suggesting that HBZ and APH-2 modulate the virus and cellular pathways differently. Herein, we examined the effect of APH-2 on several known HBZ-modulated pathways: NF-B (p65) transactivation, transforming growth factor ␤ (TGF-␤) signaling, and interferon regulatory factor 1 (IRF-1) transactivation. Like HBZ, APH-2 has the ability to inhibit p65 transactivation. Conversely, HBZ and APH-2 have divergent effects on TGF-␤ signaling and IRF-1 transactivation. Quantitative PCR and protein half-life experiments revealed a substantial disparity between HBZ and APH-2 transcript levels and protein stability, respectively. Taken together, our data further elucidate the functional differences between HBZ and APH-2 and how these differences can have profound effects on the survival of infected cells and, ultimately, pathogenesis. IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that have distinct pathological outcomes in infected hosts. Functional comparisons of HTLV-1 and HTLV-2 proteins provide a better understanding about how HTLV-1 infection is associated with disease and HTLV-2 infection is not. The HTLV genome antisense-strand genes hbz and aph-2 are often the only viral genes expressed in HTLV-infected T cells. Previously, our group found that HTLV-1 HBZ and HTLV-2 APH-2 had distinct effects in vivo and hypothesized that the differences in the interactions of HBZ and APH-2 with important cell signaling pathways dictate whether cells undergo proliferation, apoptosis, or senescence. Ultimately, these functional differences may affect how HTLV-1 causes disease but HTLV-2 generally does not. In the current study, we compared the effects of HBZ and APH-2 on several HTLV-relevant cellular pathways, including the TGF-␤ signaling, NF-B activation, and IRF-1 transactivation pathways. Human T-cell leukemia virus type 1 (HTLV-1) is a complex oncogenic deltaretrovirus that infects an estimated 15 million to 25 million people worldwide, with areas of endemic infection being found in southwestern Japan, Africa, South America, and the Caribbean Basin (1). Approximately 2 to 5% of HTLV-1-infected indi...

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“…Upon associating with HBZ, most bZIP factors are blocked from binding DNA and activating transcription, with JunD serving as the exception (60). Indeed, a complex consisting of HBZ, JunD, and Sp1 has been shown to positively regulate transcription (13,61). Based on this observation and recent evidence that Sp1 functions at enhancers (62), it is possible that an HBZ/JunD/Sp1 complex is involved in the activation of BDNF expression.…”

Section: Discussionmentioning

confidence: 99%

“…HBZ expression in cell culture models has revealed its ability to transform immortalized fibroblasts and to prolong survival of an interleukin-2 (IL-2)-dependent T-cell line following withdrawal of the cytokine (9,13). In HTLV-1-infected T-cell lines, short hairpin RNA (shRNA)-mediated knockdown of HBZ expression decreases cell proliferation, and in a mouse model, it reduces organ infiltration and tumor formation by the infected cells (14).…”

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confidence: 99%

HBZ Stimulates Brain-Derived Neurotrophic Factor/TrkB Autocrine/Paracrine Signaling To Promote Survival of Human T-Cell Leukemia Virus Type 1-Infected T Cells

Polakowski

Terol

Hoang

et al. 2014

J Virol

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Brain-derived neurotrophic factor (BDNF) is a neurotrophin that promotes neuronal proliferation, survival, and plasticity. These effects occur through autocrine and paracrine signaling events initiated by interactions between secreted BDNF and its high-affinity receptor, TrkB. A BDNF/TrkB autocrine/paracrine signaling loop has additionally been implicated in augmenting the survival of cells representing several human cancers and is associated with poor patient prognosis. Adult T-cell leukemia (ATL) is a fatal malignancy caused by infection with the complex retrovirus human T-cell leukemia virus type 1 (HTLV-1). In this study, we found that the HTLV-1-encoded protein HBZ activates expression of BDNF, and consistent with this effect, BDNF expression is elevated in HTLV-1-infected T-cell lines compared to uninfected T cells. Expression of TrkB is also higher in HTLV-1-infected T-cell lines than in uninfected T cells. Furthermore, levels of both BDNF and TrkB mRNAs are elevated in peripheral blood mononuclear cells (PBMCs) from ATL patients, and ATL patient sera contain higher concentrations of BDNF than sera from noninfected individuals. Finally, chemical inhibition of TrkB signaling increases apoptosis in HTLV-1-infected T cells and reduces phosphorylation of glycogen synthase kinase 3␤ (GSK-3␤), a downstream target in the signaling pathway. These results suggest that HBZ contributes to an active BDNF/TrkB autocrine/paracrine signaling loop in HTLV-1-infected T cells that enhances the survival of these cells. IMPORTANCEInfection with human T-cell leukemia virus type 1 (HTLV-1) can cause a rare form of leukemia designated adult T-cell leukemia (ATL). Because ATL patients are unresponsive to chemotherapy, this malignancy is fatal. As a retrovirus, HTLV-1 integrates its genome into a host cell chromosome in order to utilize host factors for replication and expression of viral proteins. However, in infected cells from ATL patients, the viral genome is frequently modified to block expression of all but a single viral protein. This protein, known as HBZ, is therefore believed to modulate cellular pathways necessary for the leukemic state and the chemotherapeutic resistance of the cell. Here we provide evidence to support this hypothesis. We found that HBZ promotes a BDNF/TrkB autocrine/paracrine signaling pathway that is known to enhance the survival and chemotherapeutic resistance of other types of cancer cells. It is possible that inhibition of this pathway may improve treatments for ATL.

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Human T-Cell Leukemia Virus Type 1 (HTLV-1) bZIP Factor Requires Cellular Transcription Factor JunD To Upregulate HTLV-1 Antisense Transcription from the 3′ Long Terminal Repeat

Cited by 55 publications

References 64 publications

The sense behind retroviral anti-sense transcription

The sense behind retroviral anti-sense transcription

Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis

HBZ Stimulates Brain-Derived Neurotrophic Factor/TrkB Autocrine/Paracrine Signaling To Promote Survival of Human T-Cell Leukemia Virus Type 1-Infected T Cells

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