Toll-like receptor 7-adapter complex modulates interferon-α production in HIV-stimulated plasmacytoid dendritic cells

• Published in: PloS one Vol. 14; no. 12; p. e0225806
• Main Authors: Patamawenu, Andy A, Wright, Nathaniel E, Shofner, Tulley, Evans, Sean, Manion, Maura M, Doria-Rose, Nicole, Migueles, Stephen A, Mendoza, Daniel, Peterson, Bennett, Wilhelm, Christopher, Rood, Julia, Berkley, Amy, Cogliano, Nancy A, Liang, C Jason, Tesselaar, Kiki, Miedema, Frank, Bess, Jr, Julian, Lifson, Jeffrey, Connors, Mark
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.12.2019; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Adapters; Adaptor Proteins, Vesicular Transport - metabolism; AIDS; Antigens; Bifurcations; Binding; Biology and Life Sciences; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; Cohort Studies; Correlation; Cytokines; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Dendritic Cells - virology; Deoxyribonucleic acid; Disease Progression; DNA; Endocytosis; Fatty Acids, Monounsaturated - pharmacology; Female; Flow cytometry; Gays & lesbians; HIV; HIV Infections - metabolism; HIV Infections - virology; HIV-1 - physiology; Human immunodeficiency virus; Humans; Immunology; Infections; Infectious diseases; Inflammation; Interferon; Interferon-alpha - biosynthesis; Interferon-alpha - metabolism; Laboratories; Ligands; Lipids; Male; Medicine and Health Sciences; Mens health; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; Pathogenesis; Pathogens; People and Places; Polymorphism; Proteins; Quaternary Ammonium Compounds - pharmacology; Receptors; Research and Analysis Methods; Ribonucleic acid; RNA; Signal Transduction - drug effects; Stimulation; TLR7 protein; TLR9 protein; Toll-Like Receptor 7 - antagonists & inhibitors; Toll-Like Receptor 7 - metabolism; Toll-Like Receptor 9 - antagonists & inhibitors; Toll-Like Receptor 9 - metabolism; Toll-like receptors; Tumor Necrosis Factor-alpha - biosynthesis; Tumor necrosis factor-α; Variation; Viral infections; Viral Load - drug effects; Viruses; α-Interferon; United States > US; Maryland; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0225806

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.