CD40L-mediated defect of the interferon system in HIV-1 infection
Zusammenfassung der Projektergebnisse
Evidence is accumulating that chronic immune activation plays an important role in the HIV-1 immunopathogenesis. One of the most proinflammatory cytokines are the type I interferons (IFN), which are secreted by plasmacytoid dendritic cells (PDC). We have identified HIV-1 infected cells as major inducers of type I IFN. Consistent with data from another group, we show that the uptake of virions into endosomal vesicles of PDC is a major factor in the HIV-1 induced IFN-alpha production. This mechanism appears to be most relevant for the lymphatic tissue, where HIV-1 infected cells come into close contact with PDC. On the other hand, we and others observed a significantly decreased response of circulating PDC to Toll-like receptor stimulation. Our project focused on CD40 ligand (CD40L), a costimulatory member of the tumor necrosis factor family. This molecule was significantly upregulated on many immune cells and also secreted as soluble variant in HIV-1 infected patients (n=52). We observed that cell-associated and soluble CD40L downregulated the CpG-induced IFN-alpha production, which could be neutralized by a CD40L antibody. This effect was more pronounced when PBMC of HIV-1 infected patients were used, most likely due to the enhanced expression of the receptor CD40 on the surface of PDC. In HIV-1 infected patients with less than 500 CD4+ T cells/pl, the IFN-alpha production was inversely correlated with the expression of CD40 on the PDC. Notably, concomitant stimulation with CD40L and CpG significantly increased the production of proinflammatory cytokines in HIV-1 infection, which was corroborated by chip analysis. Thus, our data support a model in which the HIV-1 induced chronic immune activation silences peripheral PDC innate immune responses via enhanced CD40:40L interactions. Altogether, we identified the endosome as new target for adjuvant therapies that address the chronic immune activation in HIV-1 infection. In this respect, the use of chloroquin inhibits the endosomal acidification and IFN-alpha induction; low-dose corticoid treatment reduces markers of chronic immune stimulation; and interference with enhanced CD40:CD40L interactions may be beneficial for HIV-1 infected patients whose CD4+ T cells do not recover despite HAART treatment. In conclusion, our project characterized the immune activation as a major parameter for the decline of CD4+ T cells, which may result in innovative strategies to further improve the quality of life in HIV-1 infected subjects.
Projektbezogene Publikationen (Auswahl)
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(2010). Differential effects of P-class versus other CpG oligodeoxynucleotide classes on the impaired innate immunity of plasmacytoid dendritic cells in HIV-1 infection. AIDS Res. Hum. Retrovir. 26: 161-171
Donhauser, N., Helm, M., Pritschet, K., Schuster, P., Ries, M., Korn, K., Vollmer, J. & Schmidt, B.
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(2012). Blocking type I interferon production - a new therapeutic option to reduce the HIV-1 induced immune activation. Clin. Dev. Immunol., 534929
Ries, Moritz; Pritschet, Kathrin & Schmidt, Barbara
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(2012). CD4- and dynamin-dependent endocytosis of HIV-1 into plasmacytoid dendritic cells. Virology A23: 152-164
Pritschet, Kathrin; Donhauser, Norbert; Schuster, Philipp; Ries, Moritz; Haupt, Sabrina; Kittan, Nicolai A.; Korn, Klaus; Pöhlmann, Stefan; Holland, Gudrun; Bannert, Norbert; Bogner, Elke & Schmidt, Barbara
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(2012). HIV patients treated with low-dose prednisolone exhibit lower immune activation than untreated patients. BMC. Infect. Dis. 12, 14
Kasang, Christa; Ulmer, Albrecht; Donhauser, Norbert; Schmidt, Barbara; Stich, August; Klinker, Hartwig; Kalluvya, Samuel; Koutsilieri, Eleni; Rethwilm, Axel & Scheller, Carsten
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Chronic immune activation in HIV-1 infection contributes to reduced interferon alpha production via enhanced CD40:CD40 ligand interaction. PLoS ONE 2012;7(3):e33925
Donhauser, Norbert; Pritschet, Kathrin; Helm, Martin; Harrer, Thomas; Schuster, Philipp; Ries, Moritz; Bischof, Georg; Vollmer, Jörg; Smola, Sigrun & Schmidt, Barbara
