Human T-cell leukemia virus type 2 produces a spliced antisense transcript encoding a protein that lacks a classic bZIP domain but still inhibits Tax2-mediated transcription

Halin, Marilène; Douceron, Estelle; Clerc, Isabelle; Journo, Chloé; Ko, Nga Ling; Landry, Sébastien; Murphy, Edward L.; Gessain, Antoine; Lemasson, Isabelle; Mesnard, Jean-Michel; Barbeau, Benoı̂t; Mahieux, Renaud

doi:10.1182/blood-2008-09-179879

Cited by 72 publications

(120 citation statements)

References 41 publications

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“…This level of absence is similar to the one observed with nef [13.5% (25)], an accessory gene, and higher than the ∼5% that we found for env and pol (two obligatory genes) by scanning for the presence of stop codons [all available Los Alamos database sequences (December 2015)]. This nonnegligible fraction of stops in env and pol is explained by both sequencing errors (26) and the fact that some of the sequences are defective (27). The higher level of absence with ASP ORF is explained by the fact that asp is an accessory gene.…”

Section: Resultssupporting

confidence: 86%

Concomitant emergence of the antisense protein gene of HIV-1 and of the pandemic

Cassan

Arigon-Chifolleau

Mesnard

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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114

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Recent experiments provide sound arguments in favor of the in vivo expression of the AntiSense Protein (ASP) of HIV-1. This putative protein is encoded on the antisense strand of the provirus genome and entirely overlapped by the env gene with reading frame −2. The existence of ASP was suggested in 1988, but is still controversial, and its function has yet to be determined. We used a large dataset of ∼23,000 HIV-1 and SIV sequences to study the origin, evolution, and conservation of the asp gene. We found that the ASP ORF is specific to group M of HIV-1, which is responsible for the human pandemic. Moreover, the correlation between the presence of asp and the prevalence of HIV-1 groups and M subtypes appeared to be statistically significant. We then looked for evidence of selection pressure acting on asp. Using computer simulations, we showed that the conservation of the ASP ORF in the group M could not be due to chance. Standard methods were ineffective in disentangling the two selection pressures imposed by both the Env and ASP proteins-an expected outcome with overlaps in frame −2. We thus developed a method based on careful evolutionary analysis of the presence/absence of stop codons, revealing that ASP does impose significant selection pressure. All of these results support the idea that asp is the 10th gene of HIV-1 group M and indicate a correlation with the spread of the pandemic.HIV-1 | asp and env genes | overlapping genes | phylogenetic analyses | selection pressure

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Section: Resultssupporting

confidence: 86%

Concomitant emergence of the antisense protein gene of HIV-1 and of the pandemic

Cassan

Arigon-Chifolleau

Mesnard

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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114

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Section: Importancementioning

confidence: 99%

“…For all human T-cell leukemia virus (HTLV) family members (6-15), as well as for the human immunodeficiency virus type 1 (HIV-1) (16-18), a separate promoter or promoters within the 3= LTR regulate antisense transcription. In all five of these viruses, the antisense transcripts are translated into proteins (7,8,14,15,19).For HTLV type 1 (HTLV-1), the protein produced by the single antisense gene, HTLV-1 basic leucine zipper bZIP factor (HBZ), opposes many of the functions of the HTLV-1 regulatory protein, Tax, whose gene is encoded on the sense strand. For example, Tax activates transcription from the 5= LTR promoter through formation of complexes with cellular bZIP factors in the ATF/CREB family and the coactivator p300/CBP (20), while HBZ represses transcription by binding to and sequestering these cellular proteins away from the viral promoter (7,21,22).…”

mentioning

confidence: 99%

“…With respect to expression of viral genes, a promoter within the 5= LTR of the provirus regulates sense transcription and, therefore, production of the viral gene products necessary for viral particle synthesis (gag, pro, pol, and env) as well as regulatory and accessory genes (5). For all human T-cell leukemia virus (HTLV) family members (6)(7)(8)(9)(10)(11)(12)(13)(14)(15), as well as for the human immunodeficiency virus type 1 (HIV-1) (16-18), a separate promoter or promoters within the 3= LTR regulate antisense transcription. In all five of these viruses, the antisense transcripts are translated into proteins (7,8,14,15,19).…”

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confidence: 99%

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Permissive Sense and Antisense Transcription from the 5′ and 3′ Long Terminal Repeats of Human T-Cell Leukemia Virus Type 1

Laverdure

Polakowski

Hoang

et al. 2016

J Virol

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Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus, and, as such, its genome becomes chromosomally integrated following infection. The resulting provirus contains identical 5= and 3= peripheral long terminal repeats (LTRs) containing bidirectional promoters. Antisense transcription from the 3= LTR regulates expression of a single gene, hbz, while sense transcription from the 5= LTR controls expression of all other viral genes, including tax. Both the HBZ and Tax proteins are implicated in the development of adult T-cell leukemia (ATL), a T-cell malignancy caused by HTLV-1 infection. However, these proteins appear to harbor opposing molecular functions, indicating that they may act independently and at different time points prior to leukemogenesis. Here, we used bidirectional reporter constructs to test whether transcriptional interference serves as a mechanism that inhibits simultaneous expression of Tax and HBZ. We found that sense transcription did not interfere with antisense transcription from the 3= LTR and vice versa, even with strong transcription emanating from the opposing direction. Therefore, bidirectional transcription across the provirus might not restrict hbz or tax expression. Single-cell analyses revealed that antisense transcription predominates in the absence of Tax, which transactivates viral sense transcription. Interestingly, a population of Taxexpressing cells exhibited antisense but not activated sense transcription. Consistent with the ability of Tax to induce cell cycle arrest, this population was arrested in G 0 /G 1 phase. These results imply that cell cycle arrest inhibits Tax-mediated activation of sense transcription without affecting antisense transcription, which may be important for long-term viral latency. IMPORTANCEThe chromosomally integrated form of the retrovirus human T-cell leukemia virus type 1 (HTLV-1) contains identical DNA sequences, known as long terminal repeats (LTRs), at its 5= and 3= ends. The LTRs modulate transcription in both forward (sense) and reverse (antisense) directions. We found that sense transcription from the 5= LTR does not interfere with antisense transcription from the 3= LTR, allowing viral genes encoded on opposite DNA strands to be simultaneously transcribed. Two such genes are tax and hbz, and while they are thought to function at different times during the course of infection to promote leukemogenesis of infected T cells, our results indicate that they can be simultaneously transcribed. We also found that the ability of Tax to induce cell cycle arrest inhibits its fundamental function of activating viral sense transcription but does not affect antisense transcription. This regulatory mechanism may be important for long-term HTLV-1 infection. R etroviruses express their proviral genome by taking advantage of the host cell transcription machinery. Following reverse transcription and integration within the infected cell genome, the 5= and 3= flanking regions of provirus comprise identical regions, termed long terminal repeats (LT...

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“…Originally, it was reported that HTLV-2 lacks HBZ due to the absence of the bZIP domain [22]. This finding was linked to the nonpathogenic property of HTLV-2, thereby supporting the importance of HBZ protein in tumorigenesis.…”

Section: Function Of Hbz Rnamentioning

confidence: 96%

Mystery of Human T-cell Leukemia Virus Type 1: Commentary on Two Viral Genes, Tax and HBZ

Yoshida¹

2014

J Leuk

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SummaryTwo viral genes of human T cell leukemia virus type 1, Tax and HBZ, are the focus of current research that aims to understand the oncogenic mechanisms of adult T cell leukemia, which is induced by viral infection. Tax is considered to play critical roles in tumorigenesis by modulating various cellular phenotypes, and the anti-sense gene HBZ was recently reported to counteract various functions of Tax. However, HBZ itself may also play critical roles in tumorigenesis. In this short commentary, I have summarized these apparent paradoxes and discussed the limitations of the mechanisms proposed. It will be critically important to understand the protein levels of HBZ in infected cells and the mode of action of its RNA.

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Human T-cell leukemia virus type 2 produces a spliced antisense transcript encoding a protein that lacks a classic bZIP domain but still inhibits Tax2-mediated transcription

Cited by 72 publications

References 41 publications

Concomitant emergence of the antisense protein gene of HIV-1 and of the pandemic

Concomitant emergence of the antisense protein gene of HIV-1 and of the pandemic

Permissive Sense and Antisense Transcription from the 5′ and 3′ Long Terminal Repeats of Human T-Cell Leukemia Virus Type 1

Mystery of Human T-cell Leukemia Virus Type 1: Commentary on Two Viral Genes, Tax and HBZ

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