Young women are in urgent need of female-controlled HIV prevention strategies, including antiretroviral (ARV) drugs for topical or oral pre-exposure prophylaxis (PrEP). Two daily oral ARV PrEP studies and one vaginal gel study demonstrated efficacy in preventing HIV-1 infection in women. However, two other studies of daily oral PrEP and one of daily tenofovir (TFV) gel were stopped early for futility. Prior studies suggest differences in ARV metabolism and cervical immune cell populations between otherwise similar U.S. and sub-Saharan African women, but specific differences in the genital mucosal environment that may impact ARV pharmacokinetics (PK), pharmacodynamics (PD) and efficacy are understudied. We hypothesize that young age, bacterial vaginosis (BV), semen exposure, and depot medroxyprogesterone acetate (DMPA) use are associated with increased activation of CD4-i- T cells, changes in soluble immunity, and loss of vaginal lactobacilli, which increase HIV acquisition risk and alter topical ARV PK/PD. In Project 3, mechanisms by which known HIV risks impact PK/PD will be investigated in four clinical studies: women will be studied at BV diagnosis and after successful treatment, in the setting of unprotected vaginal sexual intercourse, before and after initiation of DMPA, and by comparing sexually active adolescents to adult women. The ultimate goal is to utilize knowledge of the mechanisms underlying HIV acquisition risk to advance selection of effective, female-controlled PrEP strategies. We also propose a pre-Phase 1 tenofovir disoproxil fumarate (TDF) intravaginal ring (IVR) study in U.S. and African women at risk for HIV to assess the hypothesis that changes in mucosal immunity related to hormonal effects and/or changes in vaginal microbiota modulate PK/PD of TDF. Drug levels will be measured in plasma, genital tract secretions and epithelial tissue following 14 days of TDF ring use (Core B). Pyrosequencing and species-specific quantitative PCR assays will be performed to examine changes in vaginal microbiota that may modulate PK/PD of TDF. These studies will utilize innovative approaches to inform the development of topical ARV PrEP strategies and will investigate the key hypothesis that distinct populations of high risk women may require differential preventative strategies.

Public Health Relevance

The development of a vaginal microbicide to prevent the sexual transmission of HIV is an urgent social need. The goal of this project is to study changes in the genital tract that may affect the ability of drugs delivered locally by vaginal ring to protect U.S. and Kenyan women from HIV following sexual exposure.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-EC-A)
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Albert Einstein College of Medicine
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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
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 62:375-382
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 224:176-183
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
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
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
Petro, Christopher D; Weinrick, Brian; Khajoueinejad, Nazanin et al. (2016) HSV-2 ?gD elicits Fc?R-effector antibodies that protect against clinical isolates. JCI Insight 1:
Petro, Christopher; González, Pablo A; Cheshenko, Natalia et al. (2015) Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease. Elife 4:
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
Taneva, Ekaterina; Crooker, Kerry; Park, Sung Hyun et al. (2015) Differential Mechanisms of Tenofovir and Tenofovir Disoproxil Fumarate Cellular Transport and Implications for Topical Preexposure Prophylaxis. Antimicrob Agents Chemother 60:1667-75

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