Toll-like receptor 7-adapter complex modulates interferon-? production in HIV-stimulated plasmacytoid dendritic cells.

ABSTRACT: Plasmacytoid dendritic cells (PDCs) and their production of interferon-alpha (IFN-?) are believed to play an important role in human immunodeficiency virus, type I (HIV-1) pathogenesis. PDCs produce IFN-? and other proinflammatory cytokines through stimulation of Toll-like receptor 7 (TLR7) and TLR9 present in endosomal compartments. TLR7 recognizes single-stranded viral RNA, while TLR9 recognizes unmethylated DNA. In this study, we examined the mechanisms that may underlie variations in IFN-? production in response to HIV, and the impact of these variations on HIV pathogenesis. In four distinct cohorts, we examined PDC production of IFN-? upon stimulation with inactivated HIV-1 particles and unmethylated DNA. The signaling cascade of TLR7 bifurcates at the myeloid differentiation protein 88 (MyD88) adaptor protein to induce expression of either IFN-? or TNF-?. To determine whether variations in IFN-? production are modulated at the level of the receptor complex or downstream of it, we correlated production of IFN-? and TNF-? following stimulation of TLR7 or TLR9 receptors. Flow cytometry detection of intracellular cytokines showed strong, direct correlations between IFN-? and TNF-? expression in all four cohorts, suggesting that variations in IFN-? production are not due to variations downstream of the receptor complex. We then investigated the events upstream of TLR binding by using lipid-like vesicles to deliver TLR ligands directly to the TLR receptors, bypassing the need for CD4 binding and endocytosis. Similar tight correlations were found in IFN-? and TNF-? production in response to the TLR ligands. Taken together, these results strongly suggest that differences in IFN-? production depend on the regulatory processes at the level of the TLR7 receptor complex. Additionally, we found no association between IFN-? production before HIV infection and disease progression.

SUBMITTER: Patamawenu AA 

PROVIDER: S-EPMC6907767 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature