Effective topical pre-exposure prophylaxis (PrEP) using antiretrovirals (ARVs) depends on the interception of HIV virions at the portal of entry during sexual exposure. Recent microbicide clinical trial results underscore the need for a more complete understanding of the pharmacological and cellular events that promote HIV prevention. Accordingly, this project will study the spatiotemporal distribution of ARVs following zero-order delivery from intravaginal rings (IVRs), as well as the co-localization with HIV and CD4-F immune cells following vaginal exposure to fluorescently labeled HIV virions in pig-tailed macaques (PTM). This application addresses a series of objectives that will couple ARV eluting device design to a deeper quantitative and qualitative understanding of the biodistribution of four ARV drugs: tenofovir disoproxil fumarate (TDF) and GS7340, potent prodrugs of tenofovir (TFV), the pyrimidinedione NNRTI/entry inhibitor IQP-0528, and the CCR5 entry inhibitor maraviroc (MVC).
In aim 1, we will design and fabricate macaque-sized single agent IVRs for the controlled delivery of each of the ARVs described above to be used in PTM biodistribution studies in aim 2. We also will develop and evaluate human-sized IVRs for simultaneous delivery of a TFV prodrug with either MVC or IQP-0528.
In aim 2, we will perform rigorous biodistribution studies in PTM and evaluate ARV concentration as a function of both longitudinal position in the vaginal tract and radial depth into the tissue following administration from IVRs produced in aim 1. In addition, we will expose the vaginal tract to fluorescently-labeled HIV and assess the distribution of both HIV virions and CD4+ immunocytes.
In aim 3 we will construct mechanistic models that quantitatively describe ARV transport upon elution from IVRs and the distribution of HIV virions upon vaginal exposure to HIV infected semen. We will attempt to optimize and validate these models upon comparison with experimental data generated in aim 2 and use the resulting models to assist in the rational design of potentially efficacious dual-segment IVRs in aim 1.
The studies proposed will have a substantial impact on global women's health relevant to development of improved intravaginal microbicide delivery devices. We believe the use of promising antiretrovial agents and the critical evaluation of their transport and distribution upon elution from intravaginal rings ultimately will aid in the design of efficacious delivery systems for prevention of sexually transmitted HIV infection in women.
|Nakra, Natasha A; Madan, Rebecca Pellett; Buckley, Niall et al. (2016) Loss of Innate Host Defense Following Unprotected Vaginal Sex. J Infect Dis 213:840-7|
|Keller, Marla J; Mesquita, Pedro M; Marzinke, Mark A et al. (2016) A phase 1 randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring. AIDS 30:743-51|
|Teller, Ryan S; Malaspina, David C; Rastogi, Rachna et al. (2016) Controlling the hydration rate of a hydrophilic matrix in the core of an intravaginal ring determines antiretroviral release. J Control Release 224:176-83|
|Carias, Ann M; Allen, Shannon A; Fought, Angela J et al. (2016) Increases in Endogenous or Exogenous Progestins Promote Virus-Target Cell Interactions within the Non-human Primate Female Reproductive Tract. PLoS Pathog 12:e1005885|
|Herold, Betsy C; Chen, Beatrice A; Salata, Robert A et al. (2016) Impact of Sex on the Pharmacokinetics and Pharmacodynamics of 1% Tenofovir Gel. Clin Infect Dis 62:375-82|
|Buckley, Niall; Huber, Ashley; Lo, Yungtai et al. (2016) Association of High-Risk Human Papillomavirus with Genital Tract Mucosal Immune Factors in HIV-Infected Women. Am J Reprod Immunol 75:146-54|
|Petro, Christopher D; Weinrick, Brian; Khajoueinejad, Nazanin et al. (2016) HSV-2 Î”gD elicits FcÎ³R-effector antibodies that protect against clinical isolates. JCI Insight 1:|
|FernÃ¡ndez-Romero, JosÃ© A; Deal, Carolyn; Herold, Betsy C et al. (2015) Multipurpose prevention technologies: the future of HIV and STI protection. Trends Microbiol 23:429-36|
|Irvin, Susan C; Herold, Betsy C (2015) Molecular mechanisms linking high dose medroxyprogesterone with HIV-1 risk. PLoS One 10:e0121135|
|Murphy, Kerry; Richardson, Barbra A; Dezzutti, Charlene S et al. (2015) Levels of Genital Tract Defensins and Cytokines Differ between HIV-Uninfected US and African Women. Am J Reprod Immunol 74:313-22|
Showing the most recent 10 out of 17 publications