Open AccessToll-like receptor 7-adapter complex modulates interferon-α production in HIV-stimulated plasmacytoid dendritic cells
Author(s) -
Andy Patamawenu,
Nathaniel E. Wright,
Tulley Shofner,
Suzette M. Evans,
Maura Manion,
Nicole A. DoriaRose,
Stephen A. Migueles,
Daniel Mendoza,
Bennett A. Peterson,
Christopher Wilhelm,
Julia E. Rood,
Amy M. Berkley,
Nancy A. Cogliano,
Chi-Hui Liang,
Kiki Tesselaar,
Frank Miedema,
Julian W. Bess,
Jeffrey D. Lifson,
Mark Connors
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0225806
Subject(s) - tlr7 , plasmacytoid dendritic cell , tlr9 , biology , toll like receptor , endosome , microbiology and biotechnology , interferon , proinflammatory cytokine , receptor , interferon type i , cytokine , innate immune system , immunology , intracellular , dendritic cell , inflammation , immune system , gene expression , biochemistry , dna methylation , gene
Plasmacytoid dendritic cells (PDCs) and their production of interferon-alpha (IFN-α) are believed to play an important role in human immunodeficiency virus, type I (HIV-1) pathogenesis. PDCs produce IFN-α and other proinflammatory cytokines through stimulation of Toll-like receptor 7 (TLR7) and TLR9 present in endosomal compartments. TLR7 recognizes single-stranded viral RNA, while TLR9 recognizes unmethylated DNA. In this study, we examined the mechanisms that may underlie variations in IFN-α production in response to HIV, and the impact of these variations on HIV pathogenesis. In four distinct cohorts, we examined PDC production of IFN-α upon stimulation with inactivated HIV-1 particles and unmethylated DNA. The signaling cascade of TLR7 bifurcates at the myeloid differentiation protein 88 (MyD88) adaptor protein to induce expression of either IFN-α or TNF-α. To determine whether variations in IFN-α production are modulated at the level of the receptor complex or downstream of it, we correlated production of IFN-α and TNF-α following stimulation of TLR7 or TLR9 receptors. Flow cytometry detection of intracellular cytokines showed strong, direct correlations between IFN-α and TNF-α expression in all four cohorts, suggesting that variations in IFN-α production are not due to variations downstream of the receptor complex. We then investigated the events upstream of TLR binding by using lipid-like vesicles to deliver TLR ligands directly to the TLR receptors, bypassing the need for CD4 binding and endocytosis. Similar tight correlations were found in IFN-α and TNF-α production in response to the TLR ligands. Taken together, these results strongly suggest that differences in IFN-α production depend on the regulatory processes at the level of the TLR7 receptor complex. Additionally, we found no association between IFN-α production before HIV infection and disease progression.