Dynamics of HIV neutralization by a microbicide formulation layer: biophysical fundamentals and transport theory

Abstract

Topical microbicides are an emerging HIV/AIDS prevention modality. Microbicide biofunctionality requires creation of a chemical-physical barrier against HIV transmission. Barrier effectiveness derives from properties of the active compound and its delivery system, but little is known about how these properties translate into microbicide functionality. We developed a mathematical model simulating biologically relevant transport and HIV-neutralization processes occurring when semen-borne virus interacts with a microbicide delivery vehicle coating epithelium. The model enables analysis of how vehicle-related variables, and anti-HIV compound characteristics, affect microbicide performance. Results suggest HIV neutralization is achievable with postcoital coating thicknesses approximately 100 mum. Increased microbicide concentration and potency hasten viral neutralization and diminish penetration of infectious virus through the coating layer. Durable vehicle structures that restrict viral diffusion could provide significant protection. Our findings demonstrate the need to pair potent active ingredients with well-engineered formulation vehicles, and highlight the importance of the dosage form in microbicide effectiveness. Microbicide formulations can function not only as drug delivery vehicles, but also as physical barriers to viral penetration. Total viral neutralization with 100-mum-thin coating layers supports future microbicide use against HIV transmission. This model can be used as a tool to analyze diverse factors that govern microbicide functionality.

FIGURE 1

Geometry of model system.

FIGURE 2

Schematic of viral neutralization kinetics.

FIGURE 3

Viral neutralization model outputs. The top (−100 → 0 μm) is semen layer, and the bottom (0 → 100 μm) is formulation layer. Color-bar denotes concentration values relative to initial concentration. (A) Infectious virus concentration; reference conditions. (B) Total (grayscale) and infectious (color) virus concentration; reference conditions. (C) Microbicide concentration; reference conditions. (D) Infectious virus concentration; microbicide potency reduced 100×. (E) Infectious virus concentration; microbicide potency reduced 100× and viral and microbicide transport unhindered. (F) Infectious virus concentration; microbicide potency reduced 100×, viral and microbicide transport unhindered, and 50 μm formulation thickness. White line in panels E and F denotes 1 log reduction from seminal viral load.

FIGURE 4

Model insensitivity to trimer number. Time to total viral neutralization is shown for three different trimer populations. Model conditions are the reference conditions used in Fig. 3, A–C. Error bars represent the temporal mesh size used in the MATLAB analysis and show the uncertainty inherent in the solution. Each case is present for all points; most points overlap and are indistinguishable from each other.

FIGURE 5

Effect of changing neutralization threshold. Figures show same conditions (no viral restriction, decreased microbicide concentration) as in Fig. 3 E, except with different neutralization conditions.