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 a vaccine may block HIV transmission in the vagina. Unfortunately, the underlying mechanism(s) for protection remain unclear. Here we theoretically examined a hypothesis that builds on our recent laboratory observation: virus-specific antibodies (Ab) can trap individual virions in cervi- covaginal 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 a single virion at the same time, markedly increasing the Ab-mucin binding avidity, and thus creating an indirect virion-mucin affinity. Our model takes into account biologically relevant length and time scales, 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 can effectively immobilize HIV in a shock-like front near the semen/CVM interface, far from the vaginal epithelium. 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, geometries, kinetic and diffusional effects, providing a tool for hypothesis testing and producing quantitative insights into the dynamics of immune-mediated protection. 

 

Biophysical Journal , Volume 106 , Issue 9 , 2028 - 2036 (2014)