A safe, accessible and effective topical microbicide could significantly reduce the rate of HIV sexual transmission and potentially save millions of lives. Human monoclonal antibodies (mAbs) have high potency, specificity and an acceptable safety profile, and are leading candidates for inclusion in topical microbicides. The objective of Project 2 is to identify mechanisms by which diverse mAbs targeting different aspects of HIV-1 transmission (4E10, VRCOl, and anti-HSVgD) operate in the cervicovaginal environment.
In Specific Aim 1 we will study Mab interactions with vaginal epithelial cells. We will use human vaginal tissue and the MatTek EpiVaginal organotypic tissue model to determine Mab uptake and release pharmacodynamics and kinetics, Mab penetration depth and distribution, effects on proinflammatory cytokines and mediators of innate immunity, and effects of Mab retention by vaginal epithelial cells on HSV and HIV infection. We will also test the effects of cervical mucus and semen on mAb antiviral efficacy in these assay systems.
In Specific Aim 2 we will study the effects of mAbs on cell-associated HIV transmission .
In Specific Aim 3 we will study ex vivo efficacy of Mabs following vaginal administration to macaques and women. In collaboration with the clinical project, we will also study effects of mapp66 microbicide film use in women on markers of vaginal inflammation and innate immunity. These data, when combined with data from the other IPCP projects and cores, should provide a solid foundation for the advancement Mab-based vaginal microbicides.

Public Health Relevance

This project will shed light on mechanisms of mAb antiviral efficacy in the vaginal environment and further the development of monoclonal antibodies as topical vaginal microbicides to protect against sexually transmitted infections, including HIV/AIDS and HSV/genital herpes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096398-03
Application #
8515316
Study Section
Special Emphasis Panel (ZAI1-ESB-A)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$368,060
Indirect Cost
$45,826
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Chen, Alex; McKinley, Scott A; Shi, Feng et al. (2015) Modeling of Virion Collisions in Cervicovaginal Mucus Reveals Limits on Agglutination as the Protective Mechanism of Secretory Immunoglobulin A. PLoS One 10:e0131351
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Wang, Ying-Ying; Nunn, Kenetta L; Harit, Dimple et al. (2015) Minimizing biases associated with tracking analysis of submicron particles in heterogeneous biological fluids. J Control Release 220:37-43
Ayehunie, Seyoum; Islam, Ayesha; Cannon, Chris et al. (2015) Characterization of a Hormone-Responsive Organotypic Human Vaginal Tissue Model: Morphologic and Immunologic Effects. Reprod Sci 22:980-90
McKinley, Scott A; Chen, Alex; Shi, Feng et al. (2014) Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa. PLoS One 9:e100598
Politch, Joseph A; Marathe, Jai; Anderson, Deborah J (2014) Characteristics and quantities of HIV host cells in human genital tract secretions. J Infect Dis 210 Suppl 3:S609-15
Cone, Richard A (2014) Vaginal microbiota and sexually transmitted infections that may influence transmission of cell-associated HIV. J Infect Dis 210 Suppl 3:S616-21
Chen, Alex; McKinley, Scott A; Wang, Simi et al. (2014) Transient antibody-mucin interactions produce a dynamic molecular shield against viral invasion. Biophys J 106:2028-36

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