title: 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.
authors.affiliation: Department of Mathematics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Alex
authors.initials: A
authors.lastname: Chen
authors.affiliation: Mathematics Department, University of Florida, Gainesville, Florida.
authors.forename: Scott A
authors.initials: SA
authors.lastname: McKinley
authors.affiliation: Department of Mathematics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Simi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Mathematics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Feng
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Mathematics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mucha
authors.affiliation: Department of Mathematics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of North Carolina at Chapel Hill and North Carolina State University Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address: forest@unc.edu.
authors.forename: M Gregory
authors.initials: MG
authors.lastname: Forest
authors.affiliation: University of North Carolina at Chapel Hill and North Carolina State University Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address: lai@unc.edu.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Lai
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology / Q000378:metabolism*; D000914:Antibodies, Viral / Q000378:metabolism*; D000918:Antibody Specificity; D002584:Cervix Uteri / Q000821:virology; D005260:Female; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007700:Kinetics; D009077:Mucins / Q000378:metabolism*; D009093:Mucus / Q000821:virology; D011485:Protein Binding; D014621:Vagina / Q000821:virology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007074:Immunoglobulin G; D009077:Mucins