R-848 triggers the expression of TLR7/8 and suppresses HIV replication in monocytes

Abstract

BackgroundToll-like receptors (TLR) 7 and 8 are important in single-stranded viral RNA recognition and may play a role in HIV infection and disease progression. We analyzed TLR7/8 expression and signaling in monocytes from HIV-infected and uninfected subjects to investigate a pathway with new potential for the suppression of HIV replication.MethodsEighty-one HIV-infected and uninfected subjects from Liaoning and Henan provinces in China participated in this study. Monocytes were isolated from subjects' peripheral blood mononuclear cells by magnetic bead selection. TLR7 and TLR8 mRNA was measured using quantitative real-time reverse transcriptase PCR. R-848 (resiquimod) was used as a ligand for TLR7 and TLR8 in order to 1) assess TLR7/8-mediated monocyte responsiveness as indicated by IL-12 p40 and TNF-α secretion and 2) to examine HIV replication in cultured monocytes in the presence of R-848.ResultsWe found that expression of TLR7/8 mRNA in peripheral blood monocytes decreased with disease progression. TLR7 expression was decreased with stimulation with the TLR7/8 agonist, R-848, in vitro, whereas TLR8 expression was unaffected. Following R-848 stimulation, monocytes from HIV-infected subjects produced significantly less TNF-α than those from uninfected subjects, but trended towards greater production of IL-12 than stimulated monocytes from uninfected subjects. R-848 stimulation also suppressed HIV replication in cultured monocytes.ConclusionsOur study provides evidence that the TLR7 and TLR8 triggering can suppress HIV replication in monocytes and lead to postpone HIV disease progression, thereby offering novel targets for immunomodulatory therapy.

Transcriptomic analysis of human norovirus NS1-2 protein highlights a multifunctional role in murine monocytes

“…Hepatitis C virus encodes a non-structural disordered protein, NS5A which impairs TLR2 signalling by targeting MyD88 [69]. Studies with HIV-positive patients showed that the mRNA expression of TLR7/8 decreased during disease progression, and that activation of the TLR7/8 receptors led to suppression of HIV replication in monocytes [72]. In T cells however, HIV causes an upregulation of TLR7 resulting in T-cell anergy [73].…”

Functional polymorphisms of TLR8 are associated with hepatitis C virus infection

“…Therefore, TLR8‐mediated innate immune responses might play a key role in viral pathogenesis. Several clinical studies have demonstrated the antiviral effect of TLR8 in response to ligand stimulation . The ssRNA genome of HCV is a well‐known natural ligand for TLR8 activation .…”

Novel Drugs Targeting Toll-Like Receptors for Antiviral Therapy

“…However, the results showed a lack of adequate efficacy and severe side effects at higher doses [140]. Resiquimod treatment suppressed HIV replication in cultured human monocytes [141]. Another TLR7/8 agonist, CL097, was reported to restore defective cytokine secretion by myeloid DCs of HIV-infected pregnant women and newborns [142].…”