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

EMBO J. 2017 Oct 16;36(20):2998-3011. doi: 10.15252/embj.201695364. Epub 2017 Sep 18.

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.

Keywords: HIV‐1 and dendritic cells; HIV‐1 transmission; Snapin and vesicular trafficking; TLR8 sensing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • Dendritic Cells / immunology*
  • Dendritic Cells / virology*
  • HIV-1 / immunology
  • HIV-1 / pathogenicity*
  • Host-Pathogen Interactions*
  • Humans
  • Signal Transduction*
  • Toll-Like Receptor 8 / metabolism*
  • Vesicular Transport Proteins / metabolism*

Substances

  • SNAPIN protein, human
  • TLR8 protein, human
  • Toll-Like Receptor 8
  • Vesicular Transport Proteins