title: TLR8 activates HIV from latently infected cells of myeloid-monocytic origin directly via the MAPK pathway and from latently infected CD4+ T cells indirectly via TNF-α.
abstract: We previously showed that the TLR7/8 agonist, R-848, activated HIV from cells of myeloid-monocytic origin. In this work, we show that this effect was solely due to triggering TLR8 and that NF-κB was involved in the TLR8-mediated activation of HIV from latently infected cells of myeloid-monocytic origin. Inhibition of Erk1/2 or p38α resulted in attenuation of TLR8-mediated activation of NF-κB. Western blots confirmed that TLR8 triggering activated Erk1/2 and p38α but, surprisingly, not JNK. Although the Erk1/2 inhibitors resulted in a less attenuated TLR8-mediated NF-κB response than did p38α inhibitors, they had a more pronounced effect on blocking TLR8-mediated HIV replication, indicating that other transcription factors controlled by Erk1/2 are involved in TLR8-mediated HIV activation from latently infected cells. TNF-α, which was secreted subsequent to TLR8 triggering, contributed to the activation of HIV from the latently infected cells in an autocrine manner, revealing a bimodal mechanism by which the effect of TLR8 triggering can be sustained. We also found that TNF-α secreted by myeloid dendritic cells acted in a paracrine manner in the activation of HIV from neighboring latently infected CD4(+) T cells, which do not express TLR8. Notably, monocytes from highly active antiretroviral therapy-treated HIV(+) patients with suppressed HIV RNA showed a robust TNF-α secretion in response to TLR8 agonists, pointing to a functional TLR8 signaling axis in HIV infection. Thus, triggering TLR8 represents a very promising strategy for attacking the silent HIV from its reservoir in HIV(+) patients treated successfully with highly active antiretroviral therapy.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Erika
authors.initials: E
authors.lastname: Schlaepfer
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Speck
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000821:virology*; D002460:Cell Line; D002478:Cells, Cultured; D002999:Clone Cells; D057809:HEK293 Cells; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology*; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000821:virology*; D023461:Myeloid Progenitor Cells / Q000201:enzymology / Q000276:immunology / Q000821:virology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000502:physiology; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014775:Virus Activation / Q000276:immunology*
chemical_list: C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha