PROJECT SUIVIMARY (See Instructions): For vaginal transmission, viruses must penetrate mucus secretions to reach target cells;we recently 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. In this proposal, we seek to identify themost potent plant-produced anti-viral IgGs (PAbs) for trapping HSV and HIV in human cervicovaginal mucus as well as in mixtures of mucus and semen (Aim 1). We will also compare the distribution of PAbs delivered by vaginal ring vs. film to identify the delivery method that provides complete coverage of susceptible epithelial surface at the lowest PAb dose (Aim 2). Based on Aims 1 &2, we will test for protection against vaginal HSV challenge in vivo, as well as evaluate the safety of the PAbs and delivery vehicle (Aim 3).
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.
|Wessler, Timothy; Chen, Alex; McKinley, Scott A et al. (2016) Using Computational Modeling To Optimize the Design of Antibodies That Trap Viruses in Mucus. ACS Infect Dis 2:82-92|
|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|
|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|
|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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