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 from Griffithsia species, 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.

Griffithsin Inhibits Nipah Virus Entry and Fusion and Can Protect Syrian Golden Hamsters From Lethal Nipah Virus Challenge

“…Inhibitors of NiV entry and spread generally target protein interactions involved in receptor binding or membrane fusion processes [5][6][7][8][9][10], but the glycosylation of NiV glycoproteins presents another viable target for therapeutic development [11][12][13]. Griffithsin (GRFT) is a homodimeric high-mannose oligosaccharide binding lectin currently being evaluated in clinical trials as a topical microbicide against human immunodeficiency virus 1 (HIV-1) [14,15], and it has also demonstrated in vivo broad-spectrum activity against viruses including severe acute respiratory syndrome coronavirus, hepatitis C virus, and Japanese encephalitis virus [16][17][18][19]. In this study, we characterized the in vitro antiviral activities of GRFT and its synthetic trimeric tandemer (3mG) [20] against NiV and other viruses from 4 virus families, and tested the in vivo prophylactic potential of 3mG and an oxidation-resistant form of GRFT (Q-GRFT) against lethal NiV challenge in the Syrian golden hamster model.…”

Surface-displayed porcine reproductive and respiratory syndrome virus from cell culture onto gram-positive enhancer matrix particles

“…Besides, GRFT shows superior stability, remaining functionally stable at 80 ℃ [5], and when exposed to repeated lyophilization [25], organic solvents and proteases [24]. Researchers have confirmed that GRFT has an outstanding safety profile with little toxicity or deleterious immunological consequences [10,11], which provides further evidence in support of the clinical application of GRFT.…”

Potent antiviral activity of carbohydrate-specific algal and leguminous lectins from the Brazilian biodiversity

“…It proved 50-fold less cytotoxic than cyanovirin, and it did not increase the level of activation markers in CD4 + T lymphocytes. Scalable manufacture of cyanovirin 19 and griffithsin 20 and validation of the safety and antiviral efficacy of griffithsin in mice and rabbits as a topical microbicide has been reported by O'Keefe et al, 21,22 Takebe et al, 23 Kouokam et al, 24 Farr Zuend et al 25 and Girard et al 26 Interestingly, Castillo-Acosta et al 27 recently demonstrated that Pradimicin, a mannosespecific agent purified from Actinomyces madura, can cure mice suffering from acute sleeping sickness caused by trypanosomes. 16 It induces only minimal changes in secretion of inflammatory cytokines and chemokines by epithelial cells and human PBMCs, does not markedly upregulate T cell activation markers and gene expression, and has no measurable effect on cell viability.…”