title: Modeling of Virion Collisions in Cervicovaginal Mucus Reveals Limits on Agglutination as the Protective Mechanism of Secretory Immunoglobulin A.
abstract: Secretory immunoglobulin A (sIgA), a dimeric antibody found in high quantities in the gastrointestinal mucosa, is broadly associated with mucosal immune protection. A distinguishing feature of sIgA is its ability to crosslink pathogens, thereby creating pathogen/sIgA aggregates that are too large to traverse the dense matrix of mucin fibers in mucus layers overlying epithelial cells and consequently reducing infectivity. Here, we use modeling to investigate this mechanism of "immune exclusion" based on sIgA-mediated agglutination, in particular the potential use of sIgA to agglutinate HIV in cervicovaginal mucus (CVM) and prevent HIV transmission. Utilizing reported data on HIV diffusion in CVM and semen, we simulate HIV collision kinetics in physiologically-thick mucus layers-a necessary first step for sIgA-induced aggregation. We find that even at the median HIV load in semen of acutely infected individuals possessing high viral titers, over 99% of HIV virions will penetrate CVM and reach the vaginal epithelium without colliding with another virion. These findings imply that agglutination is unlikely to be the dominant mechanism of sIgA-mediated protection against HIV or other sexually transmitted pathogens. Rather, we surmise that agglutination is most effective against pathogens either present at exceedingly high concentrations or that possess motility mechanisms other than Brownian diffusion that significantly enhance encounter rates.
authors.affiliation: Departments of Mathematics and Applied Physical Science, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599-3250, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Chen
authors.affiliation: Mathematics Department, University of Florida, 358 Little Hall, PO Box 118105, Gainesville, FL, 32611-8105, United States of America.
authors.forename: Scott A
authors.initials: SA
authors.lastname: McKinley
authors.affiliation: Departments of Mathematics and Applied Physical Science, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599-3250, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Shi
authors.affiliation: Departments of Mathematics and Applied Physical Science, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599-3250, United States of America.
authors.forename: Simi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Departments of Mathematics and Applied Physical Science, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599-3250, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mucha
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC, 27599-7362, United States of America.
authors.forename: Dimple
authors.initials: D
authors.lastname: Harit
authors.affiliation: Departments of Mathematics and Applied Physical Science, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599-3250, United States of America; UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina-Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC, 27599, United States of America.
authors.forename: M Gregory
authors.initials: MG
authors.lastname: Forest
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC, 27599-7362, United States of America; UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina-Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC, 27599, United States of America.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Lai
mesh_terms: D000371:Agglutination / Q000276:immunology / Q000502:physiology; D002584:Cervix Uteri / Q000276:immunology / Q000502:physiology / Q000821:virology*; D005260:Female; D006678:HIV / Q000276:immunology / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology / Q000635:transmission; D006801:Humans; D007071:Immunoglobulin A, Secretory / Q000502:physiology*; D008954:Models, Biological; D009093:Mucus / Q000276:immunology / Q000502:physiology / Q000821:virology*; D012661:Semen / Q000821:virology; D014621:Vagina / Q000276:immunology / Q000502:physiology / Q000821:virology*; D019562:Viral Load / Q000276:immunology / Q000502:physiology; D014771:Virion / Q000502:physiology*
chemical_list: D007071:Immunoglobulin A, Secretory