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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.

Original publication

DOI

10.15252/embj.201695364

Type

Journal article

Journal

EMBO J

Publication Date

16/10/2017

Volume

36

Pages

2998 - 3011

Keywords

HIV‐1 and dendritic cells, HIV‐1 transmission, Snapin and vesicular trafficking, TLR8 sensing, CD4-Positive T-Lymphocytes, Cell Line, Dendritic Cells, HIV-1, Host-Pathogen Interactions, Humans, Signal Transduction, Toll-Like Receptor 8, Vesicular Transport Proteins