Snapin promotes HIV‐1 transmission from dendritic cells by dampening TLR8 signaling

• Elham Khatamzas ^[1] ; Madeleine Maria Hipp ^[1] ; Daniel Gaughan ^[1] ; Tica Pichulik ^[1] ; Alasdair Leslie ^[5] ; Ricardo A Fernandes ^[2] ; Daniele Muraro ^[1] ; Sarah Booth ^[3] ; Kieran Zausmer ^[1] ; Mei‐Yi Sun ^[1] ; Benedikt Kessler ^[5] ; Sarah Rowland‐Jones ^[4] ; Vincenzo Cerundolo ^[1] ; Alison Simmons ^[1]
  1. [1] Weatherall Institute of Molecular Medicine

     Weatherall Institute of Molecular Medicine

     Oxford District, Reino Unido

     
  2. [2] Stanford University School of Medicine

     Stanford University School of Medicine

     Estados Unidos

     
  3. [3] University of Birmingham

     University of Birmingham

     Reino Unido

     
  4. [4] University of Oxford

     University of Oxford

     Oxford District, Reino Unido

     
  5. [5] 2 KwaZulu‐Natal Research Institute for TB & HIV Durban South Africa

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 20, 2017, págs. 2998-3011
• Idioma: inglés
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• Resumen

  • 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.