A study in the new issue of the Journal of Immunology suggests that triggering a cell surface molecule called toll-like receptor 8 (TLR8) may be a means to activating latent HIV infection. Erika Schlaepfer and Roberto Speck report that, in vitro, targeting TLR8 with the drug resiquimod (aka R-848) prompted HIV activity in latently infected cells of myeloid-monocytic origin (which include monocytes, macrophages, dendritic cells, microglial cells, and hematopoietic stem cells) and also had an activating effect on HIV in latently infected CD4 T cells, by causing production of the cytokine TNF-alpha. The researchers took a very preliminary look at whether individuals on HAART might be able to respond to such an approach, and found that--solely based on TNF-alpha production--their monocytes reacted to TLR8 stimulation comparably to those from HIV negative controls.
The conclusion from the findings is that “TLR8 agonists, in combination with HAART, are intriguing compounds for purging HIV from its latent reservoirs and sanctuary sites.” Schlaepfer and Speck caution, however, that “we believe that compounds, and, in particular, TLR8 agonists, acting on the latent reservoir should be given in cycles, because a longer-term administration of any such compound might be too toxic.” Resiquimod has been studied in humans with hepatitis C infection and appeared quite potent in terms of inducing alpha interferon production (and associated side effects). The manufacturer, 3M, does not appear to be developing it further but has recently offered it to the pharmaceutical industry for license. Development of a TLR7 agonist as a hepatitis C treatment was stopped in 2007 due to toxicology studies showing "intense immune stimulation in animals."
The Journal of Immunology, April 1, 2011, vol. 186 no. 7 4314-4324
Erika Schlaepfer and Roberto F. Speck
Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, 8091 Zurich, Switzerland
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.