Griffithsin-Modified Electrospun Fibers as a Delivery Scaffold To Prevent HIV Infection

Abstract

Despite current prophylactic strategies, sexually transmitted infections (STIs) remain significant contributors to global health challenges, spurring the development of new multipurpose delivery technologies to protect individuals from and treat virus infections. However, there are few methods currently available to prevent and no method to date that cures human immunodeficiency virus (HIV) infection or combinations of STIs. While current oral and topical preexposure prophylaxes have protected against HIV infection, they have primarily relied on antiretrovirals (ARVs) to inhibit infection. Yet continued challenges with ARVs include user adherence to daily treatment regimens and the potential toxicity and antiviral resistance associated with chronic use. The integration of new biological agents may avert some of these adverse effects while also providing new mechanisms to prevent infection. Of the biologic-based antivirals, griffithsin (GRFT) has demonstrated potent inhibition of HIV-1 (and a multitude of other viruses) by adhering to and inactivating HIV-1 immediately upon contact. In parallel with the development of GRFT, electrospun fibers (EFs) have emerged as a promising platform for the delivery of agents active against HIV infection. In the study described here, our goal was to extend the mechanistic diversity of active agents and electrospun fibers by incorporating the biologic GRFT on the EF surface rather than within the EFs to inactivate HIV prior to cellular entry. We fabricated and characterized GRFT-modified EFs (GRFT-EFs) with different surface modification densities of GRFT and demonstrated their safety and efficacy against HIV-1 infection in vitro. We believe that EFs are a unique platform that may be enhanced by incorporation of additional antiviral agents to prevent STIs via multiple mechanisms. N ewly acquired sexually transmitted infections (STIs) affect 340 million people per year (1-3) and exert a significant impact on global health. Human immunodeficiency virus type 1 (HIV-1) affects ϳ35 million people globally (2-5), while untreated STIs, such as those caused by herpes simplex virus 2 (HSV-2), can enhance both the acquisition and the transmission of HIV and other agents of STIs by 2-to 4-fold (6, 7). In light of the findings of recent clinical trials, a specific, multipurpose prevention technology that has the ability to prevent multiple STIs using one delivery platform and that also increases user adherence urgently needs to be developed (8-18). In the study described here, we sought to shift current topical preexposure prophylaxis (PrEP) paradigms by integrating a multipurpose biological delivery approach to debilitate and inactivate HIV.Our long-term goal is to develop a multipurpose biologically inspired electrospun fiber (EF) prevention technology that takes cues from the innate microenvironment of the female reproductive tract to more strategically narrow the gaps in microbicide efficacy. In this work, we evaluated the potential of polymeric EF scaffolds surface modified with the po...

Multipurpose tenofovir disoproxil fumarate electrospun fibers for the prevention of HIV-1 and HSV-2 infections in vitro

“…For blank EFs, 15–20% PLGA w/w and 12–20% PLCL w/w were dissolved in either 3 mL TFE or HFIP solvent overnight while shaking at 37°C. The following day, 2 mL of PLGA or PLCL solution was aspirated into, and electrospun from, a 3 mL plastic syringe as previously described [26, 35]. All formulations were electrospun with a flow rate of 2.0 mL/hr and an applied voltage of 20 kV.…”

“…Some of the advantages of EFs include the ability to highly incorporate a diversity of active agents including drugs and biologics [25, 26], to tailor sustained-release by selecting different polymeric materials, and to maintain agent stability during the course of delivery [27, 28]. Biodegradable polymers, such as poly(lactic-co-glycolic acid (PLGA) and poly(caprolactone) (PCL), are approved by the U.S. Food and Drug Administration (FDA) for therapeutic use, indicating their proven biocompatibility and potential for translation [29].…”

On-demand microbicide products: design matters

“…This novel platform released more than 80% of its payload within 1 h in the presence of seminal hyaluronidase. Grooms et al loaded GRFT on the surface of adhesive fibers to impede HIV-1 entry into the epithelium via physical and chemical barriers [120]. This study showed the utility of fibers for biomolecule incorporation and the ability to introduce physicochemical modifications.…”

Application of electrospun fibers for female reproductive health

“…MVC has been formulated into both coaxial electrospun fibers with an ethylcellulose core and polyvinylpyrrolidone (PVP) shell [26], as well as amorphous solid dispersions in PVP and PEO [51]. Grooms et al investigated the effect of incorporating griffithsin (GRFT), a protein that has been shown to have potent activity against both HIV-1 and HSV-2, by grafting the biologic onto the surface of electrospun fibers, as opposed to encapsulating GRFT within the fiber [52]. As opposed to using drug-eluting fibers to prevent infection, Huang et al coated polystyrene fibers with poly(allylamine hydrochloride) (PAH) or dextran sulfate sodium (DSS) and observed inactivation of HIV-1 and a reduction of CD4+ TZMbl cells in the presence of replication competent HIV-1[53].…”