Abstract
Toll-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 (miRNA-28, -125b, -150, -223 and -382), 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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APOBEC-3G Deaminase
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Antigens, CD* / genetics
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Antigens, CD* / metabolism
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Antiviral Agents* / immunology
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Antiviral Agents* / metabolism
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Chemokines, CC / metabolism
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Cytidine Deaminase* / genetics
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Cytidine Deaminase* / metabolism
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GPI-Linked Proteins
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HIV Infections / virology
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HIV-1* / drug effects
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HIV-1* / pathogenicity
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HIV-1* / physiology
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Humans
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Immunity, Innate
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Interferon Type I / biosynthesis
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Interferon Type I / immunology
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Macrophages / drug effects
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Macrophages / immunology*
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Macrophages / metabolism
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Macrophages / virology*
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Membrane Glycoproteins* / genetics
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Membrane Glycoproteins* / metabolism
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Poly I-C / metabolism
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Poly I-C / pharmacology*
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RNA, Double-Stranded / genetics
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RNA, Double-Stranded / metabolism
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Toll-Like Receptor 3 / immunology
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Toll-Like Receptor 3 / metabolism*
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Virus Replication / immunology
Substances
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Antigens, CD
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Antiviral Agents
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BST2 protein, human
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Chemokines, CC
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GPI-Linked Proteins
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Interferon Type I
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Membrane Glycoproteins
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MicroRNAs
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RNA, Double-Stranded
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TLR3 protein, human
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Toll-Like Receptor 3
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APOBEC-3G Deaminase
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APOBEC3G protein, human
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Cytidine Deaminase
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Poly I-C