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

Autoři: Andy A. Patamawenu aff001;  Nathaniel E. Wright aff001;  Tulley Shofner aff001;  Sean Evans aff001;  Maura M. Manion aff001;  Nicole Doria-Rose aff001;  Stephen A. Migueles aff001;  Daniel Mendoza aff001;  Bennett Peterson aff001;  Christopher Wilhelm aff001;  Julia Rood aff001;  Amy Berkley aff001;  Nancy A. Cogliano aff001;  C. Jason Liang aff002;  Kiki Tesselaar aff003;  Frank Miedema aff003;  Julian Bess, Jr. aff004;  Jeffrey Lifson aff004;  Mark Connors aff001
Působiště autorů: HIV-Specific Immunity Section of the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America aff001;  Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America aff002;  Department of Immunology, University Medical Center Utrecht, Utrecht, Netherlands aff003;  AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, Maryland, United States of America aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


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.

Klíčová slova:

Cytokines – Flow cytometry – HIV-1 – Immune receptor signaling – Men who have sex with men – T cells – Toll-like receptors


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2019 Číslo 12
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