Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa.
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 t...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4072659?pdf=render |
| _version_ | 1818404728699092992 |
|---|---|
| author | Scott A McKinley Alex Chen Feng Shi Simi Wang Peter J Mucha M Gregory Forest Samuel K Lai |
| author_facet | Scott A McKinley Alex Chen Feng Shi Simi Wang Peter J Mucha M Gregory Forest Samuel K Lai |
| author_sort | Scott A McKinley |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T08:44:46Z |
| format | Article |
| id | doaj.art-334bb602899c4bd484c7f215d456b7ab |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T08:44:46Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-334bb602899c4bd484c7f215d456b7ab2022-12-21T23:09:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0196e10059810.1371/journal.pone.0100598Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa.Scott A McKinleyAlex ChenFeng ShiSimi WangPeter J MuchaM Gregory ForestSamuel K LaiEliciting 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.http://europepmc.org/articles/PMC4072659?pdf=render |
| spellingShingle | Scott A McKinley Alex Chen Feng Shi Simi Wang Peter J Mucha M Gregory Forest Samuel K Lai Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa. PLoS ONE |
| title | Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa. |
| title_full | Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa. |
| title_fullStr | Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa. |
| title_full_unstemmed | Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa. |
| title_short | Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa. |
| title_sort | modeling neutralization kinetics of hiv by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa |
| url | http://europepmc.org/articles/PMC4072659?pdf=render |
| work_keys_str_mv | AT scottamckinley modelingneutralizationkineticsofhivbybroadlyneutralizingmonoclonalantibodiesingenitalsecretionscoatingthecervicovaginalmucosa AT alexchen modelingneutralizationkineticsofhivbybroadlyneutralizingmonoclonalantibodiesingenitalsecretionscoatingthecervicovaginalmucosa AT fengshi modelingneutralizationkineticsofhivbybroadlyneutralizingmonoclonalantibodiesingenitalsecretionscoatingthecervicovaginalmucosa AT simiwang modelingneutralizationkineticsofhivbybroadlyneutralizingmonoclonalantibodiesingenitalsecretionscoatingthecervicovaginalmucosa AT peterjmucha modelingneutralizationkineticsofhivbybroadlyneutralizingmonoclonalantibodiesingenitalsecretionscoatingthecervicovaginalmucosa AT mgregoryforest modelingneutralizationkineticsofhivbybroadlyneutralizingmonoclonalantibodiesingenitalsecretionscoatingthecervicovaginalmucosa AT samuelklai modelingneutralizationkineticsofhivbybroadlyneutralizingmonoclonalantibodiesingenitalsecretionscoatingthecervicovaginalmucosa |