Details

Autor(en) / Beteiligte

• 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
• Apetrei, Cristian

Titel

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

Ist Teil von

• PloS one, 2019-12, Vol.14 (12), p.e0225806-e0225806

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.