title: Chronic immune activation in HIV-1 infection contributes to reduced interferon alpha production via enhanced CD40:CD40 ligand interaction.
abstract: Although a signature of increased interferon (IFN-)alpha production is observed in HIV-1 infection, the response of circulating plasmacytoid dendritic cells (PDC) to Toll-like receptor ligand stimulation is substantially impaired. This functional PDC deficit, which we specifically observed in HIV-1 infected individuals with less than 500 CD4+ T cells/µl, is not well understood. We provide evidence that the peripheral IFN-alpha production in HIV-1 infection is actively suppressed by the enhanced interaction of CD40 ligand (CD40L), a member of the tumor necrosis factor family, and its receptor CD40, which are both upregulated upon immune activation. Plasma levels of soluble CD40L were significantly higher in untreated HIV-1 infected individuals (n = 52) than in subjects on long-term antiretroviral therapy (n = 62, p<0.03) and in uninfected control donors (n = 16, p<0.001). Concomitantly, cell-associated CD40L and the expression of the receptor CD40 on the PDC were significantly upregulated in HIV-1 infection (p<0.05). Soluble and cell-associated CD40L inhibited the PDC-derived IFN-alpha production by CpG oligodeoxynucleotides dose-dependently. This suppressive effect was observed at much lower, physiological CD40L concentrations in peripheral blood mononuclear cells (PBMC) of HIV-1 infected individuals compared to controls (p<0.05). The CpG-induced IFN-alpha production in PBMC of HIV-1 infected donors was directly correlated with PDC and CD4+ T cell counts, and inversely correlated with the viral loads (p<0.001). In HIV-1 infected donors with less than 500 CD4+ T cells/µl, the CpG-induced IFN-alpha production was significantly correlated with the percentage of CD40-expressing PDC and the level of CD40 expression on these cells (p<0.05), whereas CD40L plasma levels played a minor role. In addition, low-dose CD40L contributed to the enhanced production of interleukin 6 and 8 in PBMC of HIV-1 infected donors compared to controls. Our data support the conclusion that the chronic immune activation in HIV-1 infection impairs peripheral PDC innate immune responses at least in part via enhanced CD40:CD40L interactions.
authors.affiliation: Institute of Clinical and Molecular Virology, German National Reference Centre for Retroviruses, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Donhauser
authors.forename: Kathrin
authors.initials: K
authors.lastname: Pritschet
authors.forename: Martin
authors.initials: M
authors.lastname: Helm
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrer
authors.forename: Philipp
authors.initials: P
authors.lastname: Schuster
authors.forename: Moritz
authors.initials: M
authors.lastname: Ries
authors.forename: Georg
authors.initials: G
authors.lastname: Bischof
authors.forename: Jörg
authors.initials: J
authors.lastname: Vollmer
authors.forename: Sigrun
authors.initials: S
authors.lastname: Smola
authors.forename: Barbara
authors.initials: B
authors.lastname: Schmidt
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002908:Chronic Disease; D006224:Cricetinae; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D019013:CD40 Antigens; D016898:Interferon-alpha; D015850:Interleukin-6; D016209:Interleukin-8; D009841:Oligonucleotides; D051193:Toll-Like Receptors; D023201:CD40 Ligand