Abstract
The Bowman-Birk inhibitor (BBI), a soybean-derived protease inhibitor, is known to have anti-inflammatory effect in both in vitro and in vivo systems. Macrophages play a key role in inflammation and immune activation, which is implicated in HIV disease progression. Here, we investigated the effect of BBI on HIV infection of peripheral blood monocyte-derived macrophages. We demonstrated that BBI could potently inhibit HIV replication in macrophages without cytotoxicity. Investigation of the mechanism(s) of BBI action on HIV showed that BBI induced the expression of IFN-β and multiple IFN stimulated genes (ISGs), including Myxovirus resistance protein 2 (Mx2), 2',5'-oligoadenylate synthetase (OAS-1), Virus inhibitory protein (viperin), ISG15 and ISG56. BBI treatment of macrophages also increased the expression of several known HIV restriction factors, including APOBEC3F, APOBEC3G and tetherin. Furthermore, BBI enhanced the phosphorylation of IRF3, a key regulator of IFN-β. The inhibition of IFN-β pathway by the neutralization antibody to type I IFN receptor (Anti-IFNAR) abolished BBI-mediated induction of the anti-HIV factors and inhibition of HIV in macrophages. These findings that BBI could activate IFN-β-mediated signaling pathway, initialize the intracellular innate immunity in macrophages and potently inhibit HIV at multiple steps of viral replication cycle indicate the necessity to further investigate BBI as an alternative and cost-effective anti-HIV natural product.
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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2',5'-Oligoadenylate Synthetase / genetics
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2',5'-Oligoadenylate Synthetase / immunology
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APOBEC-3G Deaminase / genetics
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APOBEC-3G Deaminase / immunology
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Adaptor Proteins, Signal Transducing
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Anti-HIV Agents / pharmacology*
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Antibodies, Neutralizing / pharmacology
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Cells, Cultured
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Cytokines / genetics
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Cytokines / immunology
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Cytosine Deaminase / genetics
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Cytosine Deaminase / immunology
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Gene Expression Regulation
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HIV-1 / drug effects*
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HIV-1 / genetics
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HIV-1 / growth & development
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Host-Pathogen Interactions / genetics
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Host-Pathogen Interactions / immunology*
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Humans
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Interferon Regulatory Factor-3 / genetics
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Interferon Regulatory Factor-3 / immunology
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Interferon-beta / antagonists & inhibitors*
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Interferon-beta / genetics
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Interferon-beta / immunology
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Macrophages / immunology*
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Macrophages / metabolism
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Macrophages / virology
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Myxovirus Resistance Proteins / genetics
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Myxovirus Resistance Proteins / immunology
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Oxidoreductases Acting on CH-CH Group Donors
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Proteins / genetics
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Proteins / immunology
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RNA-Binding Proteins
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Receptor, Interferon alpha-beta / antagonists & inhibitors
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Receptor, Interferon alpha-beta / genetics
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Receptor, Interferon alpha-beta / immunology
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Signal Transduction
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Transcription Factors / genetics
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Transcription Factors / immunology
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Trypsin Inhibitor, Bowman-Birk Soybean / pharmacology*
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Ubiquitins / genetics
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Ubiquitins / immunology
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Virus Replication / drug effects*
Substances
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Adaptor Proteins, Signal Transducing
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Anti-HIV Agents
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Antibodies, Neutralizing
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Cytokines
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IFIT1 protein, human
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IFNAR2 protein, human
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IRF3 protein, human
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Interferon Regulatory Factor-3
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MX2 protein, human
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Myxovirus Resistance Proteins
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Proteins
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RNA-Binding Proteins
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Transcription Factors
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Trypsin Inhibitor, Bowman-Birk Soybean
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Ubiquitins
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Receptor, Interferon alpha-beta
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ISG15 protein, human
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Interferon-beta
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Oxidoreductases Acting on CH-CH Group Donors
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RSAD2 protein, human
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OAS1 protein, human
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2',5'-Oligoadenylate Synthetase
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APOBEC3F protein, human
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Cytosine Deaminase
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APOBEC-3G Deaminase
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APOBEC3G protein, human