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PLoS One. 2014 Jun 26;9(6):e100598. doi: 10.1371/journal.pone.0100598. eCollection 2014.

Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa.

Author information

1
Mathematics Department, University of Florida, Gainesville, Florida, United States of America.
2
Departments of Mathematics and Applied Physical Science, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, United States of America; Statistical and Applied Mathematical Sciences Institute, Research Triangle Park, North Carolina, United States of America.
3
Departments of Mathematics and Applied Physical Science, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, United States of America.
4
Departments of Mathematics and Applied Physical Science, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, United States of America; UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, United States of America.
5
Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, United States of America; UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, United States of America.

Abstract

Eliciting broadly neutralizing antibodies (bnAb) in cervicovaginal mucus (CVM) represents a promising "first line of defense" strategy to reduce vaginal HIV transmission. However, it remains unclear what levels of bnAb must be present in CVM to effectively reduce infection. We approached this complex question by modeling the dynamic tally of bnAb coverage on HIV. This analysis introduces a critical, timescale-dependent competition: to protect, bnAb must accumulate at sufficient stoichiometry to neutralize HIV faster than virions penetrate CVM and reach target cells. We developed a model that incorporates concentrations and diffusivities of HIV and bnAb in semen and CVM, kinetic rates for binding (kon) and unbinding (koff) of select bnAb, and physiologically relevant thicknesses of CVM and semen layers. Comprehensive model simulations lead to robust conclusions about neutralization kinetics in CVM. First, due to the limited time virions in semen need to penetrate CVM, substantially greater bnAb concentrations than in vitro estimates must be present in CVM to neutralize HIV. Second, the model predicts that bnAb with more rapid kon, almost independent of koff, should offer greater neutralization potency in vivo. These findings suggest the fastest arriving virions at target cells present the greatest likelihood of infection. It also implies the marked improvements in in vitro neutralization potency of many recently discovered bnAb may not translate to comparable reduction in the bnAb dose needed to confer protection against initial vaginal infections. Our modeling framework offers a valuable tool to gaining quantitative insights into the dynamics of mucosal immunity against HIV and other infectious diseases.

PMID:
24967706
PMCID:
PMC4072659
DOI:
10.1371/journal.pone.0100598
[Indexed for MEDLINE]
Free PMC Article

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