Snapin promotes HIV-1 transmission from dendritic cells by dampening TLR8 signaling.
Khatamzas E., Hipp MM., Gaughan D., Pichulik T., Leslie A., Fernandes RA., Muraro D., Booth S., Zausmer K., Sun MY., Kessler B., Rowland-Jones S., Cerundolo V., Simmons A.
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.