We have previously shown that triggering toll-like receptor (TLR) 7/8 is able to activate HIV from cells of myeloid-monocytic origin. In this work, we identified that TLR8 triggering activated latently infected cells mainly via the MAPK pathway, in particular Erk1/2 and p38α. NFκB, its activation was partially controlled by p38α, played a minor role. TNF-α, which was secreted subsequently to TLR8 triggering, contributed to the activation of those cells in an autocrine manner, pointing to a bimodal mechanism how TLR8 triggering sustains its effect for a longer time period. Notably, we found that TNF-α secreted by myeloid dendritic cells also acts in a paracrine mode in the activation of neighboring latently infected CD4+ T cells, thus reinforcing the purging effects even on cells devoid of TLR8 expression. Thus, triggering TLR8 represent a very promising strategy for attacking the silent HIV reservoir by acting on various cell types.
This study was supported by Wolfermann-Nägeli Stiftung, Novartis Stiftung (previously Ciba-Geigy-Jubiläums-Stiftung), Olga-Mayenfisch Stiftung and Hartmann Müller-Stiftung.