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.
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.
|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:|
|Henry, Christine E; Wang, Ying-Ying; Yang, Qi et al. (2016) Anti-PEG antibodies alter the mobility and biodistribution of densely PEGylated nanoparticles in mucus. Acta Biomater 43:61-70|
|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|
|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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