HTLV-1 Tax-Mediated Inhibition of FOXO3a Activity Is Critical for the Persistence of Terminally Differentiated CD4 T Cells

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HTLV -⁠ infection contributes to the development of Adult T cell Leukemia (ATL) or the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 principally targets CD4+ T lymphocytes and causes profound changes in activation, immune function and cell death. The molecular mechanisms involved in the persistence of infected CD4+ T cells following primary HTLV-1 infection remain unclear. We demonstrate here that the Tax oncoprotein inactivates the FOXO3a transcription factor to facilitate the long-term survival of a population of highly activated and terminally differentiated T cells that maintain the capacity to spread infectious viral particles. Mechanistically, expression of Tax oncoprotein in primary human CD4+ T cells resulted in the phosphorylation-dependent inactivation of FOXO3a, via the AKT kinase. Tax-mediated CD4+ T cell persistence was also reversed by chemical inhibition of the AKT pathway, and reproduced by the expression of a dominant negative version of FOXO3a itself or by silencing its transcriptionally active form using specific siRNA. Overall this study provides new mechanistic insights used by Tax to potentiate the long-term maintenance of CD4+ T lymphocytes following HTLV-1 infection and suggests that modulation of FOXO3a activity, using a range of inhibitors targeting the PI3K-AKT-FOXO3a pathway, may offer a valuable addition to current therapeutic approaches.

Vyšlo v časopise: HTLV-1 Tax-Mediated Inhibition of FOXO3a Activity Is Critical for the Persistence of Terminally Differentiated CD4 T Cells. PLoS Pathog 10(12): e32767. doi:10.1371/journal.ppat.1004575
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004575

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