Toll-like receptor 3 signaling inhibits simian immunodeficiency virus replication in macrophages from rhesus macaques

Abstract

Toll-like receptor 3 (TLR3) recognizes double-stranded RNA and induces multiple intracellular events responsible for innate antiviral immunity against viral infections. Here we demonstrate that TLR3 signaling of monocyte-derived macrophages (MDM) from rhesus monkeys by poly I:C inhibited simian immunodeficiency virus (SIV) infection and replication. Investigation of the mechanisms showed that TLR3 activation resulted in the induction of type I and type III interferons (IFNs) and IFN-inducible antiviral factors, including APOBEC3G (A3G), tetherin and SAMHD1. In addition, poly I:C-treated macaque macrophages expressed increased levels of CC chemokines including CCL3, CCL4 and CCL5, the ligands for HIV or SIV coreceptor CCR5. Furthermore, TLR3 signaling of macaque macrophages induced the expression of cellular microRNAs (miR-29a, -29b, -146a and -9), the newly identified intracellular SIV restriction factors. TLR3 activation-mediated anti-SIV effect could be compromised by the knockdown of IRF3 and IRF7. These findings indicate that TLR3-mediated induction of multiple viral restriction factors contribute to the inhibition of SIV infection in macaque macrophages, which support future preclinical studies using rhesus macaques to determine whether in vivo TLR3 activation is safe and beneficial for treating people infected with HIV.

Protease-Activated Receptor 1 Enhances Poly I:C Induction of the Antiviral Response in Macrophages and Mice

“…[3,7,8,20,31] Furthermore, we and others showed that viral infections lead to increased TF expression in the infected tissue and activation of coagulation. [4,9–11,27] In addition, poly I:C injection leads to activation of coagulation in mice.…”

“…[3] In addition, TLR3 enhances the antiviral responses of macrophages against other viruses, such as the monkey and human immunodeficiency viruses (HIV). [7,8]…”

Toll-like receptor-3 mediates HIV-1 transactivation via NFκB and JNK pathways and histone acetylation, but prolonged activation suppresses Tat and HIV-1 replication

“…In fact, it has been shown that dsRNA can act as a small interfering RNA (siRNA) to induce the cleavage of mRNA sequence and induce transcriptional or post-transcriptional gene silencing [44–46]. Micro-RNAs, which play a critical role in RNA silencing, can also be induced by PIC and may modulate PIC antiviral effects in macrophages [17, 18, 22]. Our current study provides novel insights into the molecular basis for TLR3-mediated HIV-1 transactivation and the mechanisms of these TLR3-mediated effects are summarized in Figure 11.…”

“…However, it can also be detrimental because uncontrolled and unregulated TLR activation can result in excessive inflammation, cell injury, and tissue damage, including damage to CNS tissues [14–16]. TLR3 ligands increase the expression of inflammatory chemokines in macaques and human macrophages [17, 18] and human muscle cells [19]. TLR3 has been implicated in the pathogenesis of several viral infections, including simian immunodeficiency virus (SIV) and HIV/AIDS.…”

“…There is evidence that TLR3 ligands inhibit SIV replication in macaque cells [17, 20], inhibit HIV-1 replication in macrophages and microglia [18, 21, 22], and culture supernatant from an endothelial cell line treated with PIC also suppressed HIV-1 replication [23]. However it has been shown that TLR3 stimulates the SIV promoter [20]; and humans with chronic, untreated HIV-1 infections showed increased TLRs expression in their peripheral blood mononuclear cells (PBMC), including increased TLR2, TRL3, TLR4, TLR6, TLR7, and TLR8 [24].…”