Snapin promotes HIV‐1 transmission from dendritic cells by dampening TLR8 signaling |
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| Authors: | Daniel Gaughan Tica Pichulik Alasdair Leslie Ricardo A Fernandes Daniele Muraro Sarah Booth Kieran Zausmer Mei‐Yi Sun Benedikt Kessler Sarah Rowland‐Jones Vincenzo Cerundolo Alison Simmons |
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| Institution: | 1. MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK;2. KwaZulu‐Natal Research Institute for TB & HIV, Durban, South Africa;3. Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA;4. Immunology & Immunotherapy, College of Medical & Dental Sciences, University of Birmingham, Birmingham, UK;5. Nuffield Department of Clinical Medicine, University of Oxford, NDMRB, Oxford, UK;6. Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK |
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| Abstract: | HIV‐1 traffics through dendritic cells (DCs) en route to establishing a productive infection in T lymphocytes but fails to induce an innate immune response. Within DC endosomes, HIV‐1 somehow evades detection by the pattern‐recognition receptor (PRR) Toll‐like receptor 8 (TLR8). Using a phosphoproteomic approach, we identified a robust and diverse signaling cascade triggered by HIV‐1 upon entry into human DCs. A secondary siRNA screen of the identified signaling factors revealed several new mediators of HIV‐1 trans‐infection of CD4+ T cells in DCs, including the dynein motor protein Snapin. Inhibition of Snapin enhanced localization of HIV‐1 with TLR8+ early endosomes, triggered a pro‐inflammatory response, and inhibited trans‐infection of CD4+ T cells. Snapin inhibited TLR8 signaling in the absence of HIV‐1 and is a general regulator of endosomal maturation. Thus, we identify a new mechanism of innate immune sensing by TLR8 in DCs, which is exploited by HIV‐1 to promote transmission. |
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| Keywords: | HIV‐1 and dendritic cells HIV‐1 transmission Snapin and vesicular trafficking TLR8 sensing |
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