A critical function of toll‐like receptor‐3 in the induction of anti‐human immunodeficiency virus activities in macrophages

Abstract

SummaryToll-like receptor-3 (TLR-3) recognizes double-stranded RNA and induces multiple intracellular events responsible for innate anti-viral immunity against a number of viral infections. Activation of TLR-3 inhibits human immunodeficiency virus (HIV) replication, but the mechanism(s) underlying the action of TLR-3 activation on HIV are largely unknown. Here we demonstrate that treatment of monocyte-derived macrophages with poly I:C, a synthetic ligand for TLR-3, significantly inhibited HIV infection and replication. Investigation of the mechanisms showed that TLR-3 activation resulted in the induction of type I interferon inducible antiviral factors, including APOBEC3G and tetherin, the newly identified anti-HIV cellular proteins. In addition, poly I:C-treated macrophages expressed increased levels of CC chemokines, the ligands for CCR5. Furthermore, TLR-3 activation in macrophages induced the expression of cellular microRNAs , the newly identified intracellular HIV restriction factors. These findings indicate that TLR-3-mediated induction of multiple anti-HIV factors should be beneficial for the treatment of HIV disease where innate immune responses are compromised by the virus.

Inhibition of Anti-HIV MicroRNA Expression

“…However, we demonstrated that, although IFN-␣/␤ could induce the expression of anti-HIV RNAs (miRNA-28, miRNA-125b, miRNA-150, and miRNA-382) ( Figure 2C), they failed to induce anti-HIV miR-223 expression in monocytes (data not shown). This finding is in agreement with a previous publication 42 showing that IFN-␣/␤ had little effect on miRNA-223 expression in macrophages. Thus, it is likely that the adverse effect of morphine on anti-HIV miRNAs may be through its negative impact on endogenous IFN-␣/␤ expression in monocytes.…”

Multiple roles of the coagulation protease cascade during virus infection

“…98 Activation of TLR3 inhibits HIV replication in macrophages. 99 We observed that costimulation of PAR1 and TLR3 led to increased IFN-b-dependent responses in bone marrow-derived macrophages and dendritic cells. 46 It is therefore possible that PAR1 may also contribute to antiviral responses during HIV infection.…”

Immune activation of human brain microvascular endothelial cells inhibits HIV replication in macrophages

“…After 16 hours, the culture medium was removed and fresh medium was added (to remove the ligands that may have direct anti-HIV activity in macrophages). 21 Culture supernatant (SN) was collected at 48 hours poststimulation for an IFN-b and IFN-l enzyme-linked immunosorbent assay (ELISA) and used to treat macrophages.…”