HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells
| Autor: | Andrea L. Cox, Joseph B. Margolick, Joel N. Blankson, Guido Massaccesi, Austin W. Boesch, Margaret E. Ackerman, Zachary T. Freeman, Laura K. Cohen, Rebecca T. Veenhuis, Michael A. Chattergoon, Alessandra Tomasi, Jack Korleski |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine T cell Plasma Cells Inflammation Antigen-Antibody Complex HIV Antibodies Biology 03 medical and health sciences Viral Envelope Proteins Interferon medicine Humans Innate immune system virus diseases TLR9 Dendritic Cells General Medicine TLR7 030104 developmental biology medicine.anatomical_structure Toll-Like Receptor 7 Interferon Type I Monoclonal Immunology HIV-1 biology.protein medicine.symptom Antibody Signal Transduction Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 127:4352-4364 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci95375 |
| Popis: | Type I IFN production is essential for innate control of acute viral infection; however, prolonged high-level IFN production is associated with chronic immune activation in HIV-infected individuals. Although plasmacytoid DCs (pDCs) are a primary source of IFN, the mechanisms that regulate IFN levels following the acute phase are unknown. We hypothesized that HIV-specific Ab responses regulate late IFN production. We evaluated the mechanism through which HIV-activated pDCs produce IFN as well as how both monoclonal HIV-specific Abs and Abs produced in natural HIV infection modulated normal pDC sensing of HIV. We found that HIV-induced IFN production required TLR7 signaling, receptor-mediated entry, fusion, and viral uncoating, but not endocytosis or HIV life cycle stages after uncoating. Abs directed against the HIV envelope that do not interfere with CD4 binding markedly enhanced the IFN response, irrespective of their ability to neutralize CD4+ T cell infection. Ab-mediated enhancement of IFN production required Fc γ receptor engagement, bypassed fusion, and initiated signaling through both TLR7 and TLR9, which was not utilized in the absence of Ab. Polyclonal Abs isolated from HIV-infected subjects also enhanced pDC production of IFN in response to HIV. Our data provide an explanation for high levels of IFN production and immune activation in chronic HIV infection. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|