Elham Khatamzas, Madeleine Maria Hipp, 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
The EMBO journal 2017 Oct 16HIV-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. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.
Elham Khatamzas, Madeleine Maria Hipp, 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. Snapin promotes HIV-1 transmission from dendritic cells by dampening TLR8 signaling. The EMBO journal. 2017 Oct 16;36(20):2998-3011
PMID: 28923824
View Full Text