title: HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells.
abstract: 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.
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada; VGTI Florida, Port St. Lucie, Florida, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Olagnier
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Sze
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Samar
authors.initials: S
authors.lastname: Bel Hadj
authors.affiliation: VGTI Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Cindy
authors.initials: C
authors.lastname: Chiang
authors.affiliation: VGTI Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Courtney
authors.initials: C
authors.lastname: Steel
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Han
authors.affiliation: Immunodeficiency Service and Division of Haematology, Royal Victoria Hospital, McGill University Health Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada; VGTI Florida, Port St. Lucie, Florida, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada; VGTI Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Julien
authors.initials: J
authors.lastname: van Grevenynghe
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000473:pathology* / Q000821:virology*; D002454:Cell Differentiation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D016356:Gene Products, tax / Q000502:physiology*; D015490:HTLV-I Infections / Q000473:pathology / Q000503:physiopathology*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014764:Viral Proteins / Q000502:physiology
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016356:Gene Products, tax; D034741:RNA, Small Interfering; D014764:Viral Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt