title: Studies in a Murine Model Confirm the Safety of Griffithsin and Advocate Its Further Development as a Microbicide Targeting HIV-1 and Other Enveloped Viruses.
abstract: Griffithsin (GRFT), a lectin fromGriffithsiaspecies, inhibits human immunodeficiency virus-1 (HIV-1) replication at sub-nanomolar concentrations, with limited cellular toxicity. However, in vivo safety of GRFT is not fully understood, especially following parenteral administration. We first assessed GRFT's effects in vitro, on mouse peripheral blood mononuclear cell (mPBMC) viability, mitogenicity, and activation using flow-cytometry, as well as cytokine secretion through enzyme-linked immunosorbent assay (ELISA). Toxicological properties of GRFT were determined after a single subcutaneous administration of 50 mg/kg or 14 daily doses of 10 mg/kg in BALB/c mice. In the context of microbicide development, toxicity of GRFT at 2 mg/kg was determined after subcutaneous, intravaginal, and intraperitoneal administrations, respectively. Interestingly, GRFT caused no significant cell death, mitogenicity, activation, or cytokine release in mPBMCs, validating the usefulness of a mouse model. An excellent safety profile for GRFT was obtained in vivo: no overt changes were observed in animal fitness, blood chemistry or CBC parameters. Following GRFT treatment, reversible splenomegaly was observed with activation of certain spleen B and T cells. However, spleen tissues were not pathologically altered by GRFT (either with a single high dose or chronic doses). Finally, no detectable toxicity was found after mucosal or systemic treatment with 2 mg/kg GRFT, which should be further developed as a microbicide for HIV prevention.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, University of Louisville, Louisville, KY 40202, USA. j0kouo01@louisville.edu.
authors.forename: Joseph Calvin
authors.initials: JC
authors.lastname: Kouokam
authors.affiliation: James Graham Brown Cancer Center, University of Louisville School of Medicine, University of Louisville, Louisville, KY 40202, USA. amanda.lasnik@louisville.edu.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Lasnik
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, University of Louisville, Louisville, KY 40202, USA. kenneth.palmer@louisville.edu.|James Graham Brown Cancer Center, University of Louisville School of Medicine, University of Louisville, Louisville, KY 40202, USA. kenneth.palmer@louisville.edu.|Center for Predictive Medicine, University of Louisville, Louisville, KY 40202, USA. kenneth.palmer@louisville.edu.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Palmer
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology*; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D037121:Plant Lectins / Q000008:administration & dosage / Q000009:adverse effects* / Q000633:toxicity; D013154:Spleen / Q000473:pathology
chemical_list: D000890:Anti-Infective Agents; D037121:Plant Lectins; C499654:griffithsin protein, Griffithsia
keywords: Griffithsin; HIV; microbicide; mouse model; peripheral blood mononuclear cells (PBMCs); safety