The Microbiology/Virology Core B of this IP/CP Grant "Alternative Formulations of Tenofovir and UC781" is fully integrated into this proposal providing support and interactions with all 4 projects. This Core brings several new innovations to the safety and efficacy testing of antiretroviral (ARVs) drugs, excipients, and formulations. Microbiology/Virology Core B will support the Formulations Project 1 by screening excipients and formulated films to ensure they are not active against Lactobacillus representative of normal vaginal flora and to screen for excipient activity against sexually transmitted pathogens (STPs). The normal vaginal flora is known to be important in the prevention of infection by HIV-1 and other STPs. This Core will provide standardized testing of formulated ARV safety using ecto-cervical explant and epithelial monolayer cultures in support of Projects 1, 2, 3 and 4. ARV film efficacy and coital timing testing will be performed using the ecto-cervical explant cultures supporting Projects 2, 3, and 4 while guiding formulations in Project 1. Core B will support the animal and human trials using ex vivo biopsies to demonstrate protection from SHIV/HIV-1 infection (supporting all projects). The effects of films and gel preparation used in Projects 2 and 3 will be monitored by culture work in the Core to monitor the microflora. In Project 3, this Core will screen subjects for STPs and normal floras to assure subjects meet inclusion criterion. Cervicovaginal lavages (CVLs) samples will be collected in Projects 2, 3 and 4 and for pharmacokinetic study. This Core will utilize those CVL to determine if the and/or formulation interfere with the natural innate immunity process by examining the effects of placebo and drug containing films and gels on the killing of HIV-1, HSV, and bacteria. Also, vaginal fluid contains factors known to kill HSV as well as some bacteria. An effective microbicide can not interfere with these processes and at the same time inactivate HIV-1 or prevent its'infection. Overall, this IP/CP seeks to develop a product which prevents HIV-1 infection safely without disturbing the normal flora or other natural defenses and this Core will ensure a successful microbicide candidate is created for further clinical evaluation.

Public Health Relevance

In light of recent results from clinical trials that were stopped early due to possible harm, safety of any product is critical in moving fon/vard in development. This Core will strive to thoroughly test all microbicide films created by this grant to ensure safety and be predictive of film success when tested in women at risk for HIV-1 infection.

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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Magee-Women's Research Institute and Foundation
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Moncla, Bernard J; Chappell, Catherine A; Debo, Brian M et al. (2016) The Effects of Hormones and Vaginal Microflora on the Glycome of the Female Genital Tract: Cervical-Vaginal Fluid. PLoS One 11:e0158687
Bunge, Katherine E; Dezzutti, Charlene S; Rohan, Lisa C et al. (2016) A Phase 1 Trial to Assess the Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics of a Novel Dapivirine Vaginal Film. J Acquir Immune Defic Syndr 71:498-505
Zhou, Tian; Hu, Minlu; Pearlman, Andrew et al. (2016) Expression, regulation, and function of drug transporters in cervicovaginal tissues of a mouse model used for microbicide testing. Biochem Pharmacol 116:162-75
Fan, Maria D; Kramzer, Lindsay F; Hillier, Sharon L et al. (2016) Preferred Physical Characteristics of Vaginal Film Microbicides for HIV Prevention in Pittsburgh Women. Arch Sex Behav :
Coleman, Jenell S; Fuchs, Edward; Aung, Wutyi S et al. (2016) Feasibility of radiolabeled small molecule permeability as a quantitative measure of microbicide candidate toxicity. Contraception 93:331-6
Moncla, Bernard J; Chappell, Catherine A; Mahal, Lara K et al. (2015) Impact of bacterial vaginosis, as assessed by nugent criteria and hormonal status on glycosidases and lectin binding in cervicovaginal lavage samples. PLoS One 10:e0127091
Kramzer, Lindsay F; Cohen, Jessica; Schubert, Jesse et al. (2015) Assessing the potential of the Woman's Condom for vaginal drug delivery. Contraception 92:254-60
Hu, Minlu; Patel, Sravan Kumar; Zhou, Tian et al. (2015) Drug transporters in tissues and cells relevant to sexual transmission of HIV: Implications for drug delivery. J Control Release 219:681-96
Wang, Linlin; Koppolu, Sujeethraj; Chappell, Catherine et al. (2015) Studying the effects of reproductive hormones and bacterial vaginosis on the glycome of lavage samples from the cervicovaginal cavity. PLoS One 10:e0127021
Chappell, Catherine A; Isaacs, Charles E; Xu, Weimin et al. (2015) The effect of menopause on the innate antiviral activity of cervicovaginal lavage. Am J Obstet Gynecol 213:204.e1-6

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