title: Systemic immune activation in HIV infection is associated with decreased MDC responsiveness to TLR ligand and inability to activate naive CD4 T-cells.
abstract: BACKGROUND
  HIV infection is characterized by ineffective anti-viral T-cell responses and impaired dendritic cell (DC) functions, including response to Toll-Like Receptor (TLR) ligands. Because TLR responsiveness may affect a host's response to virus, we examined TLR ligand induced Myeloid and Plasmacytoid DC (MDC and PDC) activation of naïve T-cells in HIV+ subjects.
  
  
  METHODS
  Freshly purified MDC and PDC obtained from HIV+ subjects and healthy controls were cultured in the presence and absence of TLR ligands (poly I∶C or R-848). We evaluated indices of maturation/activation (CD83, CD86, and HLA-DR expression), cytokine secretion (IFN-alpha and IL-6), and ability to activate allogeneic naïve CD4 T-cells to secrete IFN-gamma and IL-2.
  
  
  RESULTS
  MDC from HIV+ subjects had increased spontaneous IL-6 production and increased CD83 and CD86 expression when compared to MDC of controls. MDC IL-6 expression was associated with plasma HIV level. At the same time, poly I∶C induced HLA-DR up-regulation on MDC was reduced in HIV+ persons when compared to controls. The latter finding was associated with impaired ability of MDC from HIV+ subjects to activate allogeneic naïve CD4 T-cells. PDC from HIV+ persons had increased spontaneous and TLR ligand induced IL-6 expression, and increased HLA-DR expression at baseline. The latter was associated with an intact ability of HIV PDC to activate allogeneic naïve CD4 T-cells.
  
  
  CONCLUSIONS
  These results have implications for the ability of the HIV+ host to form innate and adaptive responses to HIV and other pathogens.
authors.affiliation: Division of Infectious Diseases, Department of Pathology, Case Western Reserve University Center for AIDS Research, University Hospitals, Cleveland Ohio, United States of America.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Yonkers
authors.forename: Benigno
authors.initials: B
authors.lastname: Rodriguez
authors.forename: Robert
authors.initials: R
authors.lastname: Asaad
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
authors.forename: Donald D
authors.initials: DD
authors.lastname: Anthony
mesh_terms: D000328:Adult; D051940:B7-2 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology*; D006679:HIV Seropositivity / Q000276:immunology; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology*; D010641:Phenotype; D011070:Poly I-C / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology; D055815:Young Adult
chemical_list: D051940:B7-2 Antigen; D006684:HLA-DR Antigens; D015850:Interleukin-6; D008024:Ligands; D051193:Toll-Like Receptors; D011070:Poly I-C