title: Soybean-derived Bowman-Birk Inhibitor (BBI) Inhibits HIV Replication in Macrophages.
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.
authors.affiliation: Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, 430071, P.R. China.
authors.forename: Tong-Cui
authors.initials: TC
authors.lastname: Ma
authors.affiliation: Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, 430071, P.R. China.
authors.forename: Run-Hong
authors.initials: RH
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Jie-Liang
authors.initials: JL
authors.lastname: Li
authors.affiliation: Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, 430071, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Sang
authors.affiliation: Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, 430071, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, 430071, P.R. China.|State Key Laboratory of Virology, Wuhan University, Wuhan, Hubei, 430071, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhuang
authors.affiliation: Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, 430071, P.R. China.|State Key Laboratory of Virology, Wuhan University, Wuhan, Hubei, 430071, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hou
authors.affiliation: Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, 430071, P.R. China.|State Key Laboratory of Virology, Wuhan University, Wuhan, Hubei, 430071, P.R. China.
authors.forename: De-Yin
authors.initials: DY
authors.lastname: Guo
authors.affiliation: Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, 430071, P.R. China.|State Key Laboratory of Virology, Wuhan University, Wuhan, Hubei, 430071, P.R. China.|Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Wen-Zhe
authors.initials: WZ
authors.lastname: Ho
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000276:immunology; D000071480:APOBEC-3G Deaminase / Q000235:genetics / Q000276:immunology; D048868:Adaptor Proteins, Signal Transducing; D019380:Anti-HIV Agents / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D043525:Cytosine Deaminase / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000276:immunology; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins / Q000235:genetics / Q000276:immunology; D016601:RNA-Binding Proteins; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D014358:Trypsin Inhibitor, Bowman-Birk Soybean / Q000494:pharmacology*; D014452:Ubiquitins / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects*; D000090123:Viperin Protein
chemical_list: D015088:2',5'-Oligoadenylate Synthetase; D000071480:APOBEC-3G Deaminase; D048868:Adaptor Proteins, Signal Transducing; D019380:Anti-HIV Agents; D057134:Antibodies, Neutralizing; D016207:Cytokines; D043525:Cytosine Deaminase; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D064547:Myxovirus Resistance Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; D016601:RNA-Binding Proteins; D053633:Receptor, Interferon alpha-beta; D014157:Transcription Factors; D014358:Trypsin Inhibitor, Bowman-Birk Soybean; D014452:Ubiquitins; C484290:IFIT1 protein, human; C508033:IFNAR2 protein, human; C494232:IRF3 protein, human; C579068:MX2 protein, human; C074034:ISG15 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein; C475085:OAS1 protein, human; C492906:APOBEC3F protein, human; C464924:APOBEC3G protein, human