CD40L-mediated defect of the interferon system in HIV-1 infection
Final Report Abstract
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.
Publications
- (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.
- (2012). Blocking type I interferon production - a new therapeutic option to reduce the HIV-1 induced immune activation. Clin. Dev. Immunol., 534929
Ries, M., Pritschet, K. & Schmidt, B.
(See online at https://doi.org/10.1155/2012/534929) - (2012). CD4- and dynamin-dependent endocytosis of HIV-1 into plasmacytoid dendritic cells. Virology A23: 152-164
Pritschet, K., Donhauser, N., Schuster, P., Ries, M., Haupt, S., Kittan N. A., Korn, K., Pöhlmann, S., Holland, G., Bannert, N., Bogner, E. & Schmidt, B.
(See online at https://doi.org/10.1016/j.virol.2011.11.026) - (2012). HIV patients treated with low-dose prednisolone exhibit lower immune activation than untreated patients. BMC. Infect. Dis. 12, 14
Kasang, C., Ulmer, A., Donhauser, N., Schmidt, B., Stich, A., Klinker, H., Kalluvya, S., Koutsilieri, E., Rethwilm, A., & Scheller, C.
(See online at https://doi.org/10.1186/1471-2334-12-14) - 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, N., Pritschet, K., Helm, M., Harrer, T., Schuster, P., Ries, M., Bischof, G., Vollmer, J., Smola, S. & Schmidt, B.
(See online at https://doi.org/10.1371/journal.pone.0033925)
