title: Kruppel-like factor 2 modulates CCR5 expression and susceptibility to HIV-1 infection.
abstract: CCR5, a cell surface molecule critical for the transmission and spread of HIV-1, is dynamically regulated during T cell activation and differentiation. The molecular mechanism linking T cell activation to modulation of CCR5 expression remains undefined. Kruppel-like factor 2 (KLF2) is a transcription factor that promotes quiescence, survival, and in part by modulating chemokine receptor levels, induces homing to secondary lymphoid organs. Given the relationship between T cell activation and chemokine receptor expression, we tested whether the abundance of KLF2 after T cell activation regulates CCR5 expression and, thus, susceptibility of a T cell to CCR5-dependent HIV-1 strains (R5). We observed a strong correlation between T cell activation, expression of KLF2 and CCR5, and susceptibility to infection. To directly measure how KLF2 affects CCR5 regulation, we introduced small interfering RNA targeting KLF2 expression and demonstrated that reduced KLF2 expression also resulted in less CCR5. Chromatin immunoprecipitation assays identified KLF2 bound to the CCR5 promoter in resting but not CD3/28 activated T cells, suggesting that KLF2 directly regulates CCR5 expression. Introduction of KLF2 under control of a heterologous promoter could restore CCR5 expression and R5 susceptibility to CD3/28 costimulated T cells and some transformed cell lines. Thus, KLF2 is a host factor that modulates CCR5 expression in CD4 T cells and influences susceptibility to R5 infection.
authors.affiliation: Department of Microbiology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Max W
authors.initials: MW
authors.lastname: Richardson
authors.forename: Julie
authors.initials: J
authors.lastname: Jadlowsky
authors.forename: Chuka A
authors.initials: CA
authors.lastname: Didigu
authors.forename: Robert W
authors.initials: RW
authors.lastname: Doms
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
mesh_terms: D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002461:Cell Line, Transformed; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D016503:Drug Delivery Systems / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000209:etiology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000235:genetics; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology
chemical_list: D065100:CCR5 Receptor Antagonists; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D019713:Receptors, CCR5