For vaginal transmission, viruses must penetrate mucus secretions to reach target cells; we recentiy found that Herpes Simplex Virus (HSV) and HIV readily diffuses through human cervicovaginal mucus. Most antibodies (Ab) produced by the immune system are secreted into mucus (not blood or lymph), and topical IgG provides robust protection against vaginal viral challenges. In addition to well-known antibody functions (e.g., neutralization, complement activation, opsonization), an important yet little recognized effector function of IgG is to trap viruses in mucus. IgG bound to a virus surface may form multiple low-affinity adhesive crosslinks between the virus and the mucus gel. A sufficient number of these low-affinity crosslinks, possibly at sub-neutralizing IgG concentrations, may permanently trap the virus in the mucus gel. Our pilot observations indicate that remarkably low concentrations of specific IgGI can trap HSV-1 and virus-like particles that otherwise rapidly penetrate mucus gels. Trapping reduces the flux of virus that reaches target cells, and facilitates inactivation and clearance by additional protective mechanisms. Trapping viruses in mucus before they can reach target cells is likely essential to protect against viruses that, once established, cause incurable infections. It is likely that the most protective antibodies will be those that not only neutralize virions by blocking viral entry into target cells, but also are highly effective at trapping virions in mucus. This potential IgG trapping function in mucus has been largely unrecognized because most studies of IgG activity have not been performed in mucus geis. Hence, all monoclonal antibodies (MAbs) developed to date has been developed without considering this immune function in mucus.

Public Health Relevance

Human immunodeficiency virus (HIV) and Herpes Simplex virus (HSV) both readily move through genital tract mucus secretions to transmit infections. Recent evidence suggests viral-specific antibodies in mucus may block viruses by trapping them in mucus. This project will aid in creating antibody-based vaginal microbicides designed to protect against 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 #
5U19AI096398-02
Application #
8505991
Study Section
Special Emphasis Panel (ZAI1-ESB-A (M2))
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$160,062
Indirect Cost
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Anderson, Deborah J; Politch, Joseph A; Zeitlin, Larry et al. (2017) Systemic and topical use of monoclonal antibodies to prevent the sexual transmission of HIV. AIDS 31:1505-1517
Daggett Jr, Gregory J; Zhao, Chunxia; Connor-Stroud, Fawn et al. (2017) Comparison of the vaginal environment in rhesus and cynomolgus macaques pre- and post-lactobacillus colonization. J Med Primatol 46:232-238
Zhao, Chunxia; Gunawardana, Manjula; Villinger, Francois et al. (2017) Pharmacokinetics and Preliminary Safety of Pod-Intravaginal Rings Delivering the Monoclonal Antibody VRC01-N for HIV Prophylaxis in a Macaque Model. Antimicrob Agents Chemother 61:
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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
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
Nunn, Kenetta L; Wang, Ying-Ying; Harit, Dimple et al. (2015) Enhanced Trapping of HIV-1 by Human Cervicovaginal Mucus Is Associated with Lactobacillus crispatus-Dominant Microbiota. MBio 6:e01084-15
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
Anderson, Deborah J; Politch, Joseph A (2015) Role of Seminal Plasma in Human Female Reproductive Failure: Immunomodulation, Inflammation, and Infections. Adv Exp Med Biol 868:159-69

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