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

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-kappa B was involved in the TLR8-mediated activation of HIV from latently infected cells of myeloid-monocytic origin. Inhibition of Erk1/2 or p38 alpha resulted in attenuation of TLR8-mediated activation of NF-kappa B. Western blots confirmed that TLR8 triggering activated Erk1/2 and p38 alpha but, surprisingly, not JNK. Although the Erk1/2 inhibitors resulted in a less attenuated TLR8-mediated NF-kappa B response than did p38 alpha 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-alpha, 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-alpha 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-alpha 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. The Journal of Immunology, 2011, 186: 4314-4324.