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.
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.
|Akil, Ayman; Agashe, Hrushikesh; Dezzutti, Charlene S et al. (2015) Formulation and characterization of polymeric films containing combinations of antiretrovirals (ARVs) for HIV prevention. Pharm Res 32:458-68|
|Rinehart, Matthew; Grab, Sheila; Rohan, Lisa et al. (2014) Analysis of vaginal microbicide film hydration kinetics by quantitative imaging refractometry. PLoS One 9:e95005|
|Zhou, Tian; Hu, Minlu; Pearlman, Andrew et al. (2014) Expression and localization of p-glycoprotein, multidrug resistance protein 4, and breast cancer resistance protein in the female lower genital tract of human and pigtailed macaque. AIDS Res Hum Retroviruses 30:1106-16|
|Akil, Ayman; Devlin, Brid; Cost, Marilyn et al. (2014) Increased Dapivirine tissue accumulation through vaginal film codelivery of dapivirine and Tenofovir. Mol Pharm 11:1533-41|
|Chappell, Catherine A; Rohan, Lisa C; Moncla, Bernard J et al. (2014) The effects of reproductive hormones on the physical properties of cervicovaginal fluid. Am J Obstet Gynecol 211:226.e1-7|
|Parsons, Teresa L; Emory, Joshua F; Seserko, Lauren A et al. (2014) Dual quantification of dapivirine and maraviroc in cervicovaginal secretions from ophthalmic tear strips and polyester-based swabs via liquid chromatographic-tandem mass spectrometric (LC-MS/MS) analysis. J Pharm Biomed Anal 98:407-16|
|Dezzutti, Charlene S; Uranker, Kevin; Bunge, Katherine E et al. (2013) HIV-1 infection of female genital tract tissue for use in prevention studies. J Acquir Immune Defic Syndr 63:548-54|
|Zhou, Tian; Hu, Minlu; Cost, Marilyn et al. (2013) Short communication: expression of transporters and metabolizing enzymes in the female lower genital tract: implications for microbicide research. AIDS Res Hum Retroviruses 29:1496-503|
|Isaacs, Charles E; Xu, Weimin (2013) Theaflavin-3,3'-digallate and lactic acid combinations reduce herpes simplex virus infectivity. Antimicrob Agents Chemother 57:3806-14|
|Rinehart, Matthew T; Drake, Tyler K; Robles, Francisco E et al. (2011) Time-resolved imaging refractometry of microbicidal films using quantitative phase microscopy. J Biomed Opt 16:120510|