title: Investigation of griffithsin's interactions with human cells confirms its outstanding safety and efficacy profile as a microbicide candidate.
abstract: Many natural product-derived lectins such as the red algal lectin griffithsin (GRFT) have potent in vitro activity against viruses that display dense clusters of oligomannose N-linked glycans (NLG) on their surface envelope glycoproteins. However, since oligomannose NLG are also found on some host proteins it is possible that treatment with antiviral lectins may trigger undesirable side effects. For other antiviral lectins such as concanavalin A, banana lectin and cyanovirin-N (CV-N), interactions between the lectin and as yet undescribed cellular moieties have been reported to induce undesirable side effects including secretion of inflammatory cytokines and activation of host T-cells. We show that GRFT, unlike CV-N, binds the surface of human epithelial and peripheral blood mononuclear cells (PBMC) through an exclusively oligosaccharide-dependent interaction. In contrast to several other antiviral lectins however, GRFT treatment induces only minimal changes in secretion of inflammatory cytokines and chemokines by epithelial cells or human PBMC, has no measureable effect on cell viability and does not significantly upregulate markers of T-cell activation. In addition, GRFT appears to retain antiviral activity once bound to the surface of PBMC. Finally, RNA microarray studies show that, while CV-N and ConA regulate expression of a multitude of cellular genes, GRFT treatment effects only minimal alterations in the gene expression profile of a human ectocervical cell line. These studies indicate that GRFT has an outstanding safety profile with little evidence of induced toxicity, T-cell activation or deleterious immunological consequence, unique attributes for a natural product-derived lectin.
authors.affiliation: James Graham Brown Cancer Center and Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America.
authors.forename: Joseph Calvin
authors.initials: JC
authors.lastname: Kouokam
authors.forename: Dana
authors.initials: D
authors.lastname: Huskens
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Andrew
authors.initials: A
authors.lastname: Johannemann
authors.forename: Shonna K
authors.initials: SK
authors.lastname: Riedell
authors.forename: Wendye
authors.initials: W
authors.lastname: Walter
authors.forename: Janice M
authors.initials: JM
authors.lastname: Walker
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matoba
authors.forename: Barry R
authors.initials: BR
authors.lastname: O'Keefe
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Palmer
mesh_terms: D000328:Adult; D020418:Algal Proteins / Q000009:adverse effects / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D037102:Lectins / Q000009:adverse effects / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008856:Microscopy, Fluorescence; D037121:Plant Lectins; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014621:Vagina / Q000166:cytology / Q000187:drug effects
chemical_list: D020418:Algal Proteins; D000890:Anti-Infective Agents; D018925:Chemokines; D016207:Cytokines; D037102:Lectins; D037121:Plant Lectins; C499654:griffithsin protein, Griffithsia