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Suppression of Foxo1 Activity and Down-Modulation of CD62L (L-Selectin) in HIV-1 Infected Resting CD4 T Cells

HIV-1 hijacks and disrupts many processes in the cells it infects in order to suppress antiviral immunity and to facilitate its replication. Resting CD4 T cells are important early targets of HIV-1 infection in which HIV-1 must overcome intrinsic barriers to viral replication. Although resting CD4 T...

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Autores principales: Trinité, Benjamin, Chan, Chi N., Lee, Caroline S., Mahajan, Saurabh, Luo, Yang, Muesing, Mark A., Folkvord, Joy M., Pham, Michael, Connick, Elizabeth, Levy, David N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199762/
https://www.ncbi.nlm.nih.gov/pubmed/25330112
http://dx.doi.org/10.1371/journal.pone.0110719
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author Trinité, Benjamin
Chan, Chi N.
Lee, Caroline S.
Mahajan, Saurabh
Luo, Yang
Muesing, Mark A.
Folkvord, Joy M.
Pham, Michael
Connick, Elizabeth
Levy, David N.
author_facet Trinité, Benjamin
Chan, Chi N.
Lee, Caroline S.
Mahajan, Saurabh
Luo, Yang
Muesing, Mark A.
Folkvord, Joy M.
Pham, Michael
Connick, Elizabeth
Levy, David N.
author_sort Trinité, Benjamin
collection PubMed
description HIV-1 hijacks and disrupts many processes in the cells it infects in order to suppress antiviral immunity and to facilitate its replication. Resting CD4 T cells are important early targets of HIV-1 infection in which HIV-1 must overcome intrinsic barriers to viral replication. Although resting CD4 T cells are refractory to infection in vitro, local environmental factors within lymphoid and mucosal tissues such as cytokines facilitate viral replication while maintaining the resting state. These factors can be utilized in vitro to study HIV-1 replication in resting CD4 T cells. In vivo, the migration of resting naïve and central memory T cells into lymphoid tissues is dependent upon expression of CD62L (L-selectin), a receptor that is subsequently down-modulated following T cell activation. CD62L gene transcription is maintained in resting T cells by Foxo1 and KLF2, transcription factors that maintain T cell quiescence and which regulate additional cellular processes including survival, migration, and differentiation. Here we report that HIV-1 down-modulates CD62L in productively infected naïve and memory resting CD4 T cells while suppressing Foxo1 activity and the expression of KLF2 mRNA. Partial T cell activation was further evident as an increase in CD69 expression. Several other Foxo1- and KLF2-regulated mRNA were increased or decreased in productively infected CD4 T cells, including IL-7rα, Myc, CCR5, Fam65b, S1P(1) (EDG1), CD52, Cyclin D2 and p21(CIP1), indicating a profound reprogramming of these cells. The Foxo1 inhibitor AS1842856 accelerated de novo viral gene expression and the sequella of infection, supporting the notion that HIV-1 suppression of Foxo1 activity may be a strategy to promote replication in resting CD4 T cells. As Foxo1 is an investigative cancer therapy target, the development of Foxo1 interventions may assist the quest to specifically suppress or activate HIV-1 replication in vivo.
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spelling pubmed-41997622014-10-21 Suppression of Foxo1 Activity and Down-Modulation of CD62L (L-Selectin) in HIV-1 Infected Resting CD4 T Cells Trinité, Benjamin Chan, Chi N. Lee, Caroline S. Mahajan, Saurabh Luo, Yang Muesing, Mark A. Folkvord, Joy M. Pham, Michael Connick, Elizabeth Levy, David N. PLoS One Research Article HIV-1 hijacks and disrupts many processes in the cells it infects in order to suppress antiviral immunity and to facilitate its replication. Resting CD4 T cells are important early targets of HIV-1 infection in which HIV-1 must overcome intrinsic barriers to viral replication. Although resting CD4 T cells are refractory to infection in vitro, local environmental factors within lymphoid and mucosal tissues such as cytokines facilitate viral replication while maintaining the resting state. These factors can be utilized in vitro to study HIV-1 replication in resting CD4 T cells. In vivo, the migration of resting naïve and central memory T cells into lymphoid tissues is dependent upon expression of CD62L (L-selectin), a receptor that is subsequently down-modulated following T cell activation. CD62L gene transcription is maintained in resting T cells by Foxo1 and KLF2, transcription factors that maintain T cell quiescence and which regulate additional cellular processes including survival, migration, and differentiation. Here we report that HIV-1 down-modulates CD62L in productively infected naïve and memory resting CD4 T cells while suppressing Foxo1 activity and the expression of KLF2 mRNA. Partial T cell activation was further evident as an increase in CD69 expression. Several other Foxo1- and KLF2-regulated mRNA were increased or decreased in productively infected CD4 T cells, including IL-7rα, Myc, CCR5, Fam65b, S1P(1) (EDG1), CD52, Cyclin D2 and p21(CIP1), indicating a profound reprogramming of these cells. The Foxo1 inhibitor AS1842856 accelerated de novo viral gene expression and the sequella of infection, supporting the notion that HIV-1 suppression of Foxo1 activity may be a strategy to promote replication in resting CD4 T cells. As Foxo1 is an investigative cancer therapy target, the development of Foxo1 interventions may assist the quest to specifically suppress or activate HIV-1 replication in vivo. Public Library of Science 2014-10-16 /pmc/articles/PMC4199762/ /pubmed/25330112 http://dx.doi.org/10.1371/journal.pone.0110719 Text en © 2014 Trinité et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Trinité, Benjamin
Chan, Chi N.
Lee, Caroline S.
Mahajan, Saurabh
Luo, Yang
Muesing, Mark A.
Folkvord, Joy M.
Pham, Michael
Connick, Elizabeth
Levy, David N.
Suppression of Foxo1 Activity and Down-Modulation of CD62L (L-Selectin) in HIV-1 Infected Resting CD4 T Cells
title Suppression of Foxo1 Activity and Down-Modulation of CD62L (L-Selectin) in HIV-1 Infected Resting CD4 T Cells
title_full Suppression of Foxo1 Activity and Down-Modulation of CD62L (L-Selectin) in HIV-1 Infected Resting CD4 T Cells
title_fullStr Suppression of Foxo1 Activity and Down-Modulation of CD62L (L-Selectin) in HIV-1 Infected Resting CD4 T Cells
title_full_unstemmed Suppression of Foxo1 Activity and Down-Modulation of CD62L (L-Selectin) in HIV-1 Infected Resting CD4 T Cells
title_short Suppression of Foxo1 Activity and Down-Modulation of CD62L (L-Selectin) in HIV-1 Infected Resting CD4 T Cells
title_sort suppression of foxo1 activity and down-modulation of cd62l (l-selectin) in hiv-1 infected resting cd4 t cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199762/
https://www.ncbi.nlm.nih.gov/pubmed/25330112
http://dx.doi.org/10.1371/journal.pone.0110719
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