title: Suppression of Foxo1 activity and down-modulation of CD62L (L-selectin) in HIV-1 infected resting CD4 T cells.
abstract: 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, S1P1 (EDG1), CD52, Cyclin D2 and p21CIP1, 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.
authors.affiliation: Department of Basic Science, New York University College of Dentistry, New York, New York, United States of America.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Trinité
authors.affiliation: Department of Basic Science, New York University College of Dentistry, New York, New York, United States of America.
authors.forename: Chi N
authors.initials: CN
authors.lastname: Chan
authors.affiliation: Department of Basic Science, New York University College of Dentistry, New York, New York, United States of America.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Basic Science, New York University College of Dentistry, New York, New York, United States of America.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Mahajan
authors.affiliation: Aaron Diamond AIDS Research Center, New York, New York, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Aaron Diamond AIDS Research Center, New York, New York, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Muesing
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Joy M
authors.initials: JM
authors.lastname: Folkvord
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Pham
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Connick
authors.affiliation: Department of Basic Science, New York University College of Dentistry, New York, New York, United States of America.
authors.forename: David N
authors.initials: DN
authors.lastname: Levy
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D019041:L-Selectin / Q000096:biosynthesis* / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology; D015363:Quinolones / Q000008:administration & dosage; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: C553926:5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D015363:Quinolones; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D019041:L-Selectin