All ETDs from UAB

Advisory Committee Chair

Zdenek Hel

Advisory Committee Members

Scott Barnum

Paul Goepfert

Sonya Heath

Robin Lorenz

Holly Richter

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

The potential effect of hormonal contraception on HIV-1 acquisition and transmission represents an important public health issue. Several observational studies have suggested an association between the use of hormonal contraception, in particular injectable depot medroxyprogesterone acetate (DMPA), and an increased risk of HIV-1 acquisition and transmission. To delineate the biological mechanisms behind this phenomenon, we have recruited healthy, HIV-negative women using either DMPA, NuvaRing, or combined oral contraceptives for a vaginal biopsy and cervicovaginal lavage (CVL). Analysis of the functional capacity of circulating plasmacytoid dendritic cells (pDCs), distribution of vaginal immune cell populations, and systemic and genital levels of immune mediators was performed. The use of DMPA or NuvaRing was associated with reduced capacity of circulating pDCs to produce IFNα and TNFα in response to TLR-9 stimulation ex vivo. This was confirmed in vitro, with the progestin components of DMPA and the NuvaRing, medroxyprogesterone acetate (MPA) and etonogestrel, respectively, inhibiting the activation of T cells and pDCs isolated from healthy, premenopausal women. Systemic levels of IFNα and cervico-vaginal fluid levels of IFNα, CXCL10, MCP-1 and G-CSF were significantly reduced in DMPA users compared to women not using hormonal contraception. Additionally, DMPA use mediates effects on the structural protein expression of the vaginal epithelium. RNA-Seq analysis of gene expression in microdissected vaginal stratified squamous epithelium demonstrated that DMPA use is associated with a suppression of expression of genes critical for epithelial differentiation, formation of desmosomes, and wound healing capacity of the epithelial layer including desmoglein-1, corneodesmosin, keratins, and loricrin. DMPA or NuvaRing use is associated with suppression of human ß defensin-2 and -3 production by the vaginal epithelium, as evidenced by the analysis of epithelial gene expression, immunohistochemistry and protein levels in cervico-vaginal fluid. Evidence indicating the immunosuppressive properties of DMPA strongly suggests that DMPA should be discontinued and replaced with other forms of effective and safe contraception. We demonstrate that norethisterone (NET) and levonorgestrel (LNG) did not exhibit detectable immunosuppressive activity on pDCs and T cells in vitro. These progestins should be considered as alternative contraceptives to DMPA; however, more in vivo testing is needed to confirm this data.

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