Compartmental Analysis of Intravaginal HIV Transport and Neutralization by Microbicides

Abstract

Microbicides are topically acting molecules intended to inhibit HIV-transmission by acting within luminal fluids and/or vaginal mucosa. Gels are a promising microbicide delivery modality, with clinical evidence that they can reduce the rate of sexually-transmitted HIV in women (Karim et al, 2010). We created a model of interacting vaginal co-transport of HIV virions and gel-introduced microbicides in four compartments: semen, gel, vaginal fluid, mucosa. Imaging studies of gel distribution have shown that mucosal surfaces has incomplete gel coating; there can be substantial surface area directly exposed to semen. HIV and microbicide transport occur by diffusion and convection, the latter modeled using Taylor dispersion theory. Here, the active microbicide is an HIV entry inhibitor that must collide with virions in sufficient numbers before they arrive at the mucosal surface to prevent transmission. Key model output is the time-dependent number of non-neutralized virions arriving at the tissue surface. Key inputs are: fraction of surface with coating; coating thickness distribution; viral load in semen; microbicide concentration in gel; parameters of HIV neutralization mechanism; HIV and microbicide diffusion coefficients in gel, semen and vaginal fluid; and time interval between gel application and semen deposition. Results show that infectious HIV transport to tissue is largely over uncoated regions, since HIV diffusion in gel is significantly restricted (Lai et al, 2010). If fractional coated area >90%, most reasonable combinations of system parameters cause substantial HIV neutralization, with small numbers (∼ 1000) of still-infectious virions reaching tissue. Lower fractional coated areas and increased HIV diffusion coefficients result in increased flux of infectious virions to tissue in a multivariate manner delineated by the model. This modeling helps improve our understanding of how HIV transmission can be reduced by rationally designed microbicides. [Support: NIH AI077289 and Duke CFAR].