Fig 9. The proposed mechanism of the effect of exNef on inflammation.

Nef released in exosomes from HIV–infected cells is taken up by bystander cells where it reduces the amount of ABCA1 by previously described mechanisms: displacement of ABCA1 from rafts with subsequent degradation of ABCA1 and preventing interaction of newly synthesized ABCA1 with calnexin, also followed by its degradation. Reduction of ABCA1 inhibits activation of Cdc42, which in turn decreases formation of filamentous actin enhancing formation of lipid rafts. Increase in lipid raft abundance leads to recruitment into rafts of TREM-1 and TLR4, leading to the activation of TLR4, phosphorylation of ERK1/2, activation of inflammasomes and stimulation of secretion of pro-inflammatory cytokines.