Transient antibody-mucin interactions produce a dynamic molecular shield against viral invasion

Abstract

Given the difficulty in finding a cure for HIV/AIDS, a promising prevention strategy to reduce HIV transmission is to directly block infection at the portal of entry. The recent Thai RV144 trial offered the first evidence that an antibody-based vaccine may block heterosexual HIV transmission. Unfortunately, the underlying mechanism(s) for protection remain unclear. Here we theoretically examine a hypothesis that builds on our recent laboratory observation: virus-specific antibodies (Ab) can trap individual virions in cervicovaginal mucus (CVM), thereby reducing infection in vivo. Ab are known to have a weak-previously considered inconsequential-binding affinity with the mucin fibers that constitute CVM. However, multiple Ab can bind to the same virion at the same time, which markedly increases the overall Ab-mucin binding avidity, and creates an inheritable virion-mucin affinity. Our model takes into account biologically relevant length and timescales, while incorporating known HIV-Ab affinity and the respective diffusivities of viruses and Ab in semen and CVM. The model predicts that HIV-specific Ab in CVM leads to rapid formation and persistence of an HIV concentration front near the semen/CVM interface, far from the vaginal epithelium. Such an HIV concentration front minimizes the flux of HIV virions reaching target cells, and maximizes their elimination upon drainage of genital secretions. The robustness of the result implies that even exceedingly weak Ab-mucin affinity can markedly reduce the flux of virions reaching target cells. Beyond this specific application, the model developed here is adaptable to other pathogens, mucosal barriers, and geometries, as well as kinetic and diffusional effects, providing a tool for hypothesis testing and producing quantitative insights into the dynamics of immune-mediated protection.

Figure 1

(A) Schematic depicting multiple HIV-bound IgG immobilizing HIV virions in CVM via multiple low-affinity IgG-mucin bonds. (B) Schematic of our model for diffusion of HIV from seminal secretions across a cervicovaginal mucus (CVM) layer supplemented with anti-HIV IgG en route to the underlying vaginal epithelium. To reduce infection, IgG must bind to HIV in sufficient quantities to neutralize or to trap the virions in mucus before HIV virions successfully penetrate CVM and reach the vaginal epithelium. (C) Predicted concentration profiles of IgG in the semen and CVM layers at various times postejaculation. To see this figure in color, go online.

Figure 2

Dynamics of HIV virions diffusing across CVM supplemented with NIH45-46. (A and B) The kinetics of accumulation of NIH45-46 IgG on example HIV virions, and their spatial location over time (C and D). Virion paths start at either 50 μm (A and C) or 0 μm (B and D) from the semen/CVM interface. Paths were chosen so that the passage time was within one standard deviation of the expected mean passage time (α = 1). The α = 0.9 path is derived from the same realization as for α = 1, with the modification that a virion in the CVM has a probability αⁿ of free diffusion.

Figure 3

HIV concentration profiles across genital secretions coating the vaginal epithelium for (A) α = 1, (B) α = 0.95, (C) α = 0.9, and (D) α = 0.8, at an initial NIH45-46 concentration of 5 μg/mL. The virus concentration curves are shown at 0, 40, 80, and 120 min. (E and F) Percentage of virus in CVM within 1 and 5 μm, respectively, of the semen/CVM interface over time.

Figure 4

(A–D) Percentage of viral load in semen, CVM, and cells over time for (A) α = 1, (B) α = 0.95, (C) α = 0.9, and (D) α = 0.8 and an initial Ab concentration of [NIH45-46] = 5 μg/mL. (E) Percent of viral load arriving at epithelium in 2 h for various values of α, initial Ab concentration [NIH45-46]. (F) HIV infectivity (defined as the fraction of Ab-free Env spikes on virions arriving at the epithelium compared with [NIH45-46] = 0 μg/mL, α = 1) for various α, initial Ab concentration [NIH45-46]. (G) Predicted IC₅₀, IC₈₀ (see Table 1), [NIH45-46] = 5 μg/mL.