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In vitro Study on Synergistic Interactions Between Free and Encapsulated Q-Griffithsin and Antiretrovirals Against HIV-1 Infection

Authors Minooei F, Fried JR, Fuqua JL, Palmer KE, Steinbach-Rankins JM

Received 22 October 2020

Accepted for publication 19 December 2020

Published 15 February 2021 Volume 2021:16 Pages 1189—1206


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Phong A Tran

Farnaz Minooei,1 Joel R Fried,1 Joshua L Fuqua,2– 4 Kenneth E Palmer,3– 5 Jill M Steinbach-Rankins2– 5

1Department of Chemical Engineering, University of Louisville Speed School of Engineering, Louisville, KY, USA; 2Department of Bioengineering, University of Louisville Speed School of Engineering, Louisville, KY, USA; 3Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; 4Center for Predictive Medicine, University of Louisville, Louisville, KY, USA; 5Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA

Correspondence: Jill M Steinbach-Rankins
Department of Bioengineering, University of Louisville Speed School of Engineering, 505 S. Hancock St., Room 623, Louisville, KY, 40202, USA
Tel +1 502-852-5486

Introduction: Human immunodeficiency virus (HIV) remains a persistent global challenge, impacting 38 million people worldwide. Antiretrovirals (ARVs) including tenofovir (TFV), raltegravir (RAL), and dapivirine (DAP) have been developed to prevent and treat HIV-1 via different mechanisms of action. In parallel, a promising biological candidate, griffithsin (GRFT), has demonstrated outstanding preclinical safety and potency against HIV-1. While ARV co-administration has been shown to enhance virus inhibition, synergistic interactions between ARVs and the oxidation-resistant variant of GRFT (Q-GRFT) have not yet been explored. Here, we co-administered Q-GRFT with TFV, RAL, and DAP, in free and encapsulated forms, to identify unique protein-drug synergies.
Methods: Nanoparticles (NPs) were synthesized using a single or double-emulsion technique and release from each formulation was assessed in simulated vaginal fluid. Next, each ARV, in free and encapsulated forms, was co-administered with Q-GRFT or Q-GRFT NPs to evaluate the impact of co-administration in HIV-1 pseudovirus assays, and the combination indices were calculated to identify synergistic interactions. Using the most synergistic formulations, we investigated the effect of agent incorporation in NP-fiber composites on release properties. Finally, NP safety was assessed in vitro using MTT assay.
Results: All active agents were encapsulated in NPs with desirable encapsulation efficiency (15– 100%), providing ∼ 20% release over 2 weeks. The co-administration of free Q-GRFT with each free ARV resulted in strong synergistic interactions, relative to each agent alone. Similarly, Q-GRFT NP and ARV NP co-administration resulted in synergy across all formulations, with the most potent interactions between encapsulated Q-GRFT and DAP. Furthermore, the incorporation of Q-GRFT and DAP in NP-fiber composites resulted in burst release of DAP and Q-GRFT with a second phase of Q-GRFT release. Finally, all NP formulations exhibited safety in vitro.
Conclusions: This work suggests that Q-GRFT and ARV co-administration in free or encapsulated forms may improve efficacy in achieving prophylaxis.

Keywords: griffithsin, nanoparticles, electrospun fibers, antiretrovirals, synergy, HIV-1 prevention, microbicide

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