title: Soluble CD40 ligand contributes to dendritic cell-mediated T-cell dysfunction in HIV-1 infection.
abstract: OBJECTIVE
  Plasma soluble CD40 ligand (sCD40L) is increased during HIV-1 infection, but it is unknown whether it circulates in monomeric or multimeric forms, and whether the circulating forms have differential effects on myeloid dendritic cell function and adaptive regulation.
  
  
  METHODS
  sCD40L forms were measured in plasma samples from HIV-infected donors. The effects of sCD40L forms on dendritic cell function were measured in vitro.
  
  
  METHODS
  To delineate which forms of sCD40L are present in plasma from HIV-infected donors, immunoblots were performed following enrichment of plasma for medium and low-abundance proteins. Dendritic cells from seronegative donors were exposed to multiple forms of sCD40L prior to Toll-like receptor stimulation and dendritic cell function and adaptive regulation was assessed in vitro.
  
  
  RESULTS
  Monomeric and multimeric forms of sCD40L were identified in plasma from antiretroviral therapy-treated HIV-infected donors. Although monomeric and multimeric forms of sCD40L had differential effects on dendritic cell activation when given alone, both strongly suppressed secretion of the Th1 skewing cytokine, interleukin-12, upon subsequent Toll-like receptor stimulation. Furthermore, dendritic cells exposed to both monomeric and multimeric sCD40L induced regulatory T-cell formation and T-cell anergy.
  
  
  CONCLUSIONS
  Elevated sCD40L during HIV infection impairs dendritic cell function, contributing to innate and adaptive immune dysfunction. Antiretroviral adjunctive therapies that decrease sCD40L may provide immune modulatory benefits.
authors.affiliation: aDivision of Infectious Diseases, Department of Medicine bDivision of Hematology and Oncology, Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai cDivision of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Miller
authors.forename: Ramya
authors.initials: R
authors.lastname: Gopal
authors.forename: Vanessa
authors.initials: V
authors.lastname: Valdes
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Berger
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
authors.forename: Meagan P
authors.initials: MP
authors.lastname: O'Brien
mesh_terms: D023201:CD40 Ligand / Q000097:blood*; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D003713:Dendritic Cells / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D051193:Toll-Like Receptors; D023201:CD40 Ligand; D018664:Interleukin-12