Modulation of mucosal and systemic immunity by hormonal contraceptive use ABSTRACT Growing feminization of the HIV pandemic has created an even greater need for research that will improve our understanding of risk factors promoting transmission of HIV to women. Many epidemiological investigations indicate there may be connections between hormonal contraceptive use and enhanced susceptibility for HIV acquisition, but substantial study limitations hypothesis of our proposal is that progestin-based hormonal contraceptives inhibit genital tract immune responses and tip the balance of protective immunity at genital mucosal surfaces towards acquisition of infection. This hypothesis is based on novel demonstration in our murine model of viral mucosal infection that dendritic cell (DC) activation, virus-specific T cell expansion, and memory T cell development are suppressed among mice administered depot-medroxyprogesterone acetate (DMPA) prior to infection. Notably, our preliminary studies were able to demonstrate that antigen presenting cells (APCs) activated directly ex vivo from women using DMPA also have a decreased ability to induce allogeneic T cell proliferation. These results helped generate a fresh approach to this research question that focuses on the immunomodulatory effects of DMPA, oral contraceptives (OC), and levonorgestrel-containng intrauterine devices (LNG-IUD) that may impair host responses against viral pathogens. Incorporating methods similar to ones developed in our preliminary investigations, we will utilize APCs isolated from the blood and cervixes of women before (enrollment) and after (1 month follow-up visit) they initiate use of OC, DMPA, or LNG-IUD in order to determine the effects of these drugs on APC ability to up-regulate co-stimulatory molecule expression and induce ex vivo T cell proliferation (Aim 1). Cervical secretions collected from women at both study visits will be used to compare concentrations of several innate immune response elements, while cervical tissue will also be used to compare inflammatory and antiviral cytokine production by cervical cells stimulated ex vivo with a Toll-lik receptor 3 agonist (Aim 2).
In Aim 2, we will also determine if OC, DMPA, or LNG-IUD use elicits any decreases in cervical epithelial layer thickness or any increases in the exposure of Langerhans cells to the mucosal surface. Completion of these research aims would provide the first comparative evaluation of the capacity of OCP, DMPA, and LNG-IUD to suppress host responses needed to combat genital tract infection, and would also supply healthcare providers more informed recommendations regarding the most appropriate choices for hormonal contraception among women at risk for HIV.

Public Health Relevance

Increasing feminization of the HIV epidemic demands more complete delineation of the relationships between hormonal contraceptive use and susceptibility to HIV infection. This project investigates changes to systemic and genital tract immune responses elicited by oral, injectable, and intrauterine hormonal contraceptives that may impair a woman's ability to combat viral infection. Completion of this proposal will determine biological plausibility of suspected associations between hormonal contraceptive and increased susceptibility to HIV, and supply healthcare providers more informed recommendations regarding apt hormonal contraceptive choices among women at risk for HIV infection.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZHD1-DSR-W (50))
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Yoshinaga, Koji
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University of Pittsburgh
Schools of Medicine
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Vicetti Miguel, Rodolfo D; Quispe Calla, Nirk E; Dixon, Darlene et al. (2017) IL-4-secreting eosinophils promote endometrial stromal cell proliferation and prevent Chlamydia-induced upper genital tract damage. Proc Natl Acad Sci U S A 114:E6892-E6901
Quispe Calla, Nirk E; Vicetti Miguel, Rodolfo D; Trout, Wayne et al. (2017) HIV and Hormonal Contraception: Bench and Bedside. J Acquir Immune Defic Syndr 74:e85-e86
Vicetti Miguel, Rodolfo D; Quispe Calla, Nirk E; Cherpes, Thomas L (2017) Setting Sights on Chlamydia Immunity's Central Paradigm: Can We Hit a Moving Target? Infect Immun 85:
Quispe Calla, N E; Vicetti Miguel, R D; Boyaka, P N et al. (2016) Medroxyprogesterone acetate and levonorgestrel increase genital mucosal permeability and enhance susceptibility to genital herpes simplex virus type 2 infection. Mucosal Immunol 9:1571-1583
Quispe Calla, Nirk E; Vicetti Miguel, Rodolfo D; Mei, Ao et al. (2016) Dendritic cell function and pathogen-specific T cell immunity are inhibited in mice administered levonorgestrel prior to intranasal Chlamydia trachomatis infection. Sci Rep 6:37723
Vicetti Miguel, Rodolfo D; Henschel, Kevin J; DueƱas Lopez, Fiorela C et al. (2015) Fluorescent labeling reliably identifies Chlamydia trachomatis in living human endometrial cells and rapidly and accurately quantifies chlamydial inclusion forming units. J Microbiol Methods 119:79-82
Quispe Calla, N E; Ghonime, M G; Cherpes, T L et al. (2015) Medroxyprogesterone acetate impairs human dendritic cell activation and function. Hum Reprod 30:1169-77
Vicetti Miguel, Rodolfo D; Harvey, Stephen A K; LaFramboise, William A et al. (2013) Human female genital tract infection by the obligate intracellular bacterium Chlamydia trachomatis elicits robust Type 2 immunity. PLoS One 8:e58565
Vicetti Miguel, Rodolfo D; Maryak, Samantha A; Cherpes, Thomas L (2012) Brefeldin A, but not monensin, enables flow cytometric detection of interleukin-4 within peripheral T cells responding to ex vivo stimulation with Chlamydia trachomatis. J Immunol Methods 384:191-5
Cherpes, Thomas L; Matthews, Dean B; Maryak, Samantha A (2012) Neonatal herpes simplex virus infection. Clin Obstet Gynecol 55:938-44

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