Plasma factors during chronic HIV-1 infection impair IL-12 secretion by myeloid dendritic cells via a virus-independent pathway

Elizabeth A. Miller, Meredith R. Spadaccia, Meagan P. O'Brien, Linda Rolnitzky, Rachel Sabado, Olivier Manches, Davor Frleta, Nina Bhardwaj

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Objective: Myeloid dendritic cell (mDC) dysfunction during HIV infection may hinder the formation of both innate and adaptive immune responses and contribute to pathogenesis. Our objective was to determine whether circulating factors during chronic HIV infection impair mDC function with respect to secretion of IL-12, a pro-Th1 cytokine, and T-cell stimulatory capacity. Particular focus was placed on the effect of combination antiretroviral therapy (cART) and the role of HIV itself on mDC function. Methods: Monocyte-derived DC (moDC) from uninfected donors were exposed to plasma from HIV-infected individuals before Tolllike receptor (TLR) stimulation. Cytokine secretion was measured via cytokine bead arrays, and T-cell proliferation and IFNg secretion was evaluated after coculture with naive CD4+ T cells. Expression of genes central to TLR-mediated signal transduction was analyzed via quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) arrays and western blot. Results: Exposure of monocyte-derived DC to plasma from untreated HIV-infected donors suppressed secretion of IL-12, and impaired Th1-skewing of CD4+ T cells. The suppressive effect was less by plasma donors receiving cART. Removal of virus from plasma did not relieve suppression nor was IL-12 secretion decreased on addition of HIV to control plasma. On a transcriptional level, decreased expression of IKKβ, a key regulator in the TLR/NF-kappaB signaling pathway, corresponded to suppressed cytokine secretion. Conclusions: Plasma factors during chronic HIV infection impair mDC function in a manner that likely impacts the formation of immune responses to HIV, opportunistic pathogens, and vaccines. Despite partial alleviation by cART, this suppression was not directly mediated by HIV.

Original languageEnglish
Pages (from-to)535-544
Number of pages10
JournalJournal of Acquired Immune Deficiency Syndromes
Volume61
Issue number5
DOIs
StatePublished - 15 Dec 2012
Externally publishedYes

Keywords

  • HIV-1
  • I-kappaB kinase
  • IL-12
  • Innate immunity
  • Myeloid dendritic cell
  • Tolllike receptor

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