HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells.
The mechanisms involved in the persistence of activated CD4+ T lymphocytes following primary human T leukemia/lymphoma virus type 1 (HTLV-1) infection remain unclear. Here, we demonstrate that the HTLV-1 Tax oncoprotein modulates phosphorylation and transcriptional activity of the FOXO3a transcripti...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-12-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004575&type=printable |
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| _version_ | 1841527135894765568 |
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| author | David Olagnier Alexandre Sze Samar Bel Hadj Cindy Chiang Courtney Steel Xiaoying Han Jean-Pierre Routy Rongtuan Lin John Hiscott Julien van Grevenynghe |
| author_facet | David Olagnier Alexandre Sze Samar Bel Hadj Cindy Chiang Courtney Steel Xiaoying Han Jean-Pierre Routy Rongtuan Lin John Hiscott Julien van Grevenynghe |
| author_sort | David Olagnier |
| collection | DOAJ |
| description | The mechanisms involved in the persistence of activated CD4+ T lymphocytes following primary human T leukemia/lymphoma virus type 1 (HTLV-1) infection remain unclear. Here, we demonstrate that the HTLV-1 Tax oncoprotein modulates phosphorylation and transcriptional activity of the FOXO3a transcription factor, via upstream activation of the AKT pathway. De novo HTLV-1 infection of CD4+ T cells or direct lentiviral-mediated introduction of Tax led to AKT activation and AKT-dependent inactivation of FOXO3a, via phosphorylation of residues Ser253 and Thr32. Inhibition of FOXO3a signalling led to the long-term survival of a population of highly activated, terminally differentiated CD4+Tax+CD27negCCR7neg T cells that maintained the capacity to disseminate infectious HTLV-1. CD4+ T cell persistence was reversed by chemical inhibition of AKT activity, lentiviral-mediated expression of a dominant-negative form of FOXO3a or by specific small interfering RNA (siRNA)-mediated silencing of FOXO3a. Overall this study provides new mechanistic insight into the strategies used by HTLV-1 to increase long-term maintenance of Tax+CD4+ T lymphocytes during the early stages of HTLV-1 pathogenesis. |
| format | Article |
| id | doaj-art-dbc7aea3169c4e23b8f97b7b628bf276 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2014-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-dbc7aea3169c4e23b8f97b7b628bf2762025-01-16T05:30:58ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-12-011012e100457510.1371/journal.ppat.1004575HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells.David OlagnierAlexandre SzeSamar Bel HadjCindy ChiangCourtney SteelXiaoying HanJean-Pierre RoutyRongtuan LinJohn HiscottJulien van GrevenyngheThe mechanisms involved in the persistence of activated CD4+ T lymphocytes following primary human T leukemia/lymphoma virus type 1 (HTLV-1) infection remain unclear. Here, we demonstrate that the HTLV-1 Tax oncoprotein modulates phosphorylation and transcriptional activity of the FOXO3a transcription factor, via upstream activation of the AKT pathway. De novo HTLV-1 infection of CD4+ T cells or direct lentiviral-mediated introduction of Tax led to AKT activation and AKT-dependent inactivation of FOXO3a, via phosphorylation of residues Ser253 and Thr32. Inhibition of FOXO3a signalling led to the long-term survival of a population of highly activated, terminally differentiated CD4+Tax+CD27negCCR7neg T cells that maintained the capacity to disseminate infectious HTLV-1. CD4+ T cell persistence was reversed by chemical inhibition of AKT activity, lentiviral-mediated expression of a dominant-negative form of FOXO3a or by specific small interfering RNA (siRNA)-mediated silencing of FOXO3a. Overall this study provides new mechanistic insight into the strategies used by HTLV-1 to increase long-term maintenance of Tax+CD4+ T lymphocytes during the early stages of HTLV-1 pathogenesis.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004575&type=printable |
| spellingShingle | David Olagnier Alexandre Sze Samar Bel Hadj Cindy Chiang Courtney Steel Xiaoying Han Jean-Pierre Routy Rongtuan Lin John Hiscott Julien van Grevenynghe HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells. PLoS Pathogens |
| title | HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells. |
| title_full | HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells. |
| title_fullStr | HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells. |
| title_full_unstemmed | HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells. |
| title_short | HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells. |
| title_sort | htlv 1 tax mediated inhibition of foxo3a activity is critical for the persistence of terminally differentiated cd4 t cells |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004575&type=printable |
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