GalNAc-Specific Soybean Lectin Inhibits HIV Infection of Macrophages through Induction of Antiviral Factors

Abstract

Although it has been shown that some mannose-binding lectins (MBLs) exhibit significant activity against HIV infection, little is known about whether -acetylgalactosamine (GalNAc)-binding lectins have the ability to inhibit HIV infection. Here, we demonstrate that a soybean-derived lectin (SBL) with GalNAc-binding affinity could potently suppress HIV infection of macrophages in a dose-dependent fashion. Unlike the MBLs, which block HIV only through binding to the glycosylated envelope proteins (gp120 and gp41) of the virus, SBL inhibited HIV at multiple steps of the virus infection/replication cycle. SBL could activate the beta interferon (IFN-β)-STAT signaling pathway, resulting in the upregulation of a number of antiviral interferon-stimulated genes (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 presaturation of GalNAc-binding capacity could compromise SBL-mediated induction of the antiviral factors. Furthermore, SBL exerted its anti-HIV activity in the low nanomolar range with no mitogenic effect on CD4 T cells, a major advantage in the development of SBL as a potential anti-HIV agent compared with MBLs. These data indicate a necessity to further investigate SBL as an alternative and cost-effective anti-HIV natural product. Mannose-binding lectins (MBLs) can block the attachment of HIV to target cells and have been suggested as anti-HIV microbicides. However, the mitogenic effect of MBLs on CD4 T cells limits this potential in clinical settings. Lectins with galactose (Gal)- or -acetylgalactosamine (GalNAc)-binding specificity are another important category of carbohydrate-binding proteins (CBP). Compared to high-mannose N-linked glycans, GalNAc-type glycans present much less in HIV gp120 or gp41 glycosylation. Here, we demonstrate that GalNAc-specific soybean lectin (SBL) triggers antiviral signaling via recognition of the cell surface galactosyl group of macrophages, which results in the suppression of HIV at multiple steps. More importantly, SBL has no mitogenic effect on the activation of CD4 T cells, a major advantage in the development of Gal/GalNAc-specific lectins as naturopathic anti-HIV agents.

Chemical modification of the adeno-associated virus capsid to improve gene delivery

“…The coupling reaction of the sugar on the AAV surface was first studied by dot blot analysis using soybean lectin which binds selectively to GalNAc residues 37 and the A20 antibody. The positive dots with the A20 antibody, which recognized the entire capsid, indicated that AAV2 remained intact after the coupling procedure with 4 , 5 or 8 and subsequent dialysis ( Fig.…”

BanLec-eGFP Chimera as a Tool for Evaluation of Lectin Binding to High-Mannose Glycans on Microorganisms

“…Antiviral lectins interact with glycan structures added as post-translational modifications to the viral envelope proteins [ 34 , 36 ]. The anti-HIV activity has been reported for the mannose-binding lectins such as the lectin from banana (BanLec), microvirin from the cyanobacterium Microcystis aeruginosa , scytovirin from the cyanobacteria Scytonema varium , lectin from snowdrop (GNA), and lectin from the red alga Griffithsia sp.…”

“…(Griffithsin—GRFT). They have been proposed as antiviral microbicides in the prevention of HIV transmission [ 36 , 37 ]. Anti-influenza activity has been shown for some lectins, such as BanLec [ 38 ], cyanovirin-N [ 39 ], NICTABA ( Nicotiana tabacum agglutinin), and UDA ( Urtica dioica agglutinin) [ 40 ].…”

Bottlebrush Glycopolymers from 2-Oxazolines and Acrylamides for Targeting Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Nonintegrin and Mannose-Binding Lectin

“…However, binding affinity is achieved by the multivalent nature of the protein and the resulting “glycocluster effect” in combination with the sugar density of the ligand. , The binding behavior of carbohydrate-binding proteins is of particular interest because cancer cells and other pathogens show alterations in the typical glycosylation patterns on the cell surface (glycocalyx). These abnormalities in the glycocalyx can be targeted by certain lectins, paving the way for lectin-based diagnostics and therapies. − Furthermore, multiple lectins are known to interact with a number of viruses, making them promising targets for the treatment and prevention of viral infections. , Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and mannose-binding lectin (MBL) are the subjects of extensive research due to their key role in pathogen response after viral infections, including HIV. − The tetrameric structure of DC-SIGN leads to great selectivity toward mannose- and/or fucose-containing glycopolymers . Furthermore, MBL was found to play an important role in the immunological defense by binding to numerous parasites, viruses, and bacteria, such as Neisseria meningitis, Ebola, and Influenza A. − MBL is presenting different structural forms ranging from dimers to hexamers based on oligomers exhibiting three peptide chains with a carbohydrate-recognition domain, which binds to multiple sugars and glycopolymers with high affinities …”

“…5−8 Furthermore, multiple lectins are known to interact with a number of viruses, making them promising targets for the treatment and prevention of viral infections. 9,10 Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and mannose-binding lectin (MBL) are the subjects of extensive research due to their key role in pathogen response after viral infections, including HIV. 11−15 The tetrameric structure of DC-SIGN leads to great selectivity toward mannose-and/or fucose-containing glycopolymers.…”