Natural Products Inhibit HIV Infection

Part I Epigallocatechin Gallate Inhibits Macaque SEVI-mediated Enhancement of SIV or SHIV InfectionSexual transmission contributes to more than 80%of new HIV infections.During sexual intercourse,semen is not only an important carrier,but also contains a factor that can enhance HIV infection up to 105-fold in cultures.This factor is termed SEVI(Semen-derived Enhancer of Virus Infection),which is composed of proteolytic fragments(PAP248-286)from prostatic acid phosphatase(PAP)in semen.Due to its high positive charge and the unique "cross-β" structure,the amyloid fibril serves as a cationic bridge that promotes virus onto the cell surface and enhances HIV infection.Although in vitro studies have clearly shown that human SEVI could enhance HIV infection/replication,in vivo investigation on the role of human SEVI in enhancing intravaginal/SIV infection in the macaque model has conflicting results.It is likely that the exposure of macaque vaginal mucosa to human semen/SEVI can induce local inflammation and immune reactions to the foreign proteins.Therefore,it is appropriate to use macaque SEVI for studies of SIV or SHIV sexual transmission with macaque models.In this study,we firtly identified the amino acid sequence of macaque PAP248-286 and found that there is one amino acid difference at the site of 277 between human PAP248-286 and macaque PAP248-286.The synthetic macaque PAP248-286 peptide could formed the amyloid fibrils,which is termed macaque SEVI.Importantly,macaque SEVI significantly enhanced SIV or SHIV infection of TZM-bl cells and macaque PBMCs.Epigallocatechin gallate(EGCG),the most abundant catechin in green tea has been shown to have antioxidant and anti-inflammation effects.Here,we reported that EGCG could block macaque SEVI-mediated enhancement of SIV or SHIV infection.Mechanistically,EGCG degraded the formation of macaque SEVI amyloid fibrils that facilitates HIV attachment to the target cells.In summary,the finding that macaque SEVI could enhance SIV or SHIV infection indicates the possibility to use the macaque SEVI in vivo studies with the macaque models.In addition,future studies are necessary to examine whether EGCG can be used as an effective microbicide for preventing SIV or SHIV mucosal transmission.Part Ⅱ GalNAc-Specific Soybean Lectin Inhibits HIV Infection of Macrophages through Induction of Antiviral FactorsGlycans account for almost 50%molecular weight of the heavily glycosylated HIV envelop glycoproteins(gp120 and gp41),and about 33%of these glycans are high-mannose type.The lectins with mannose-binding capacity(MBLs),have been reported to have significant anti-HIV activity via the interaction with the mannose moieties on viral envelop proteins.Therefore,MBLs have been now suggested for use as antiviral microbicides to prevent HIV sexual transmission.As compared to high-mannose N-linked glycans,GalNAc-type glycans present much less in HIV gp120 or gp41 glycosylation.Of note,mammalian cell surface exhibits a variety of glycans including galactosyl groups affiliated with membrane-bound proteins or glycolipids,which are involved in essential biological functions.Although much of studies have been focused on the binding to HIV envelop glycoproteins by the MBLs,there is little information about the impact of lectin’s binding to the target cell glycans on HIV infection.We here demonstrate that a soybean-derived lectin(SBL)with GalNAc-binding affinity could potently suppress HIV infection of macrophages in a dose-depend fashion.Unlike the MBLs that block HIV only through binding to the glycosylated envelope proteins of the virus,SBL inhibited HIV at multiple steps of the virus infection/replication cycle.SBL activated IFN-β-STAT signaling pathway,resulting in the upregulation of a number of antiviral ISGs in macrophages.In addition,SBL treatment of macrophages induced the production of C-C chemokines,which bind to HIV entry coreceptor CCR5.Deglycosylation of cell surface galactosyl moieties or pre-saturation of GalNAc-binding capacity could compromise SBL-mediated induction of the antiviral factors.Importantly,SBL exerted its anti-HIV activity in the low nanomolar range with no mitogenicity to CD4+ T cells,a major advantage in the development of SBL as a potential anti-HIV agents as compare with MBLs.Furthermore,we revealed that two other Gal/GalNAc-specific plant lectins(DBA,RCA I)can also induce antiviral Mx2 and MIP-1β expression in macrophages.In this regard,the ability of SBL to suppress HIV infection or other Gal/GalNAc-specific lectin to induce antiviral factors without inducing systemic activation of CD4+ T cells is an important property that potentiating the development of Gal/GalNAc-specific lectins as cost-effective anti-HIV natural products.