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Use of Injectable Depot Medroxyprogesterone Acetate (DMPA) Downregulates
Vaginal Epithelial Barrier Genes - Similarly to Mucosal Inflammation
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Reported by Jules Levin
HIVR4P Oct 18-20 2016 Chicago
http://webcasts.hivr4p.org/console/player/33025?mediaType=audio&
some slides were not available but you listen to entire talk at this link above
Irina A. Zalenskaya1, Neelima Chandra1, Nazita Yousefieh1, Suzanne S. Jackson1, Sharon M. Anderson1, Christine K. Mauck1, Andrea R. Thurman1, Gustavo F. Doncel1
1CONRAD, Eastern Virginia Medical School, United States
Background: Cervicovaginal inflammation and certain hormonal contraceptives (HC), in particular DMPA, have been associated with increased acquisition of HIV. But what is the common mechanism underlying this increased susceptibility? To answer this question, we conducted gene profiling of human vaginal tissues after six weeks of HC use and compared HC-altered transcriptomes with a previously defined gene signature of vaginal response to pro-inflammatory compounds.
Methods: Thirty women received DMPA injection and 32 women used combined (levonorgestrel/ethinyl estradiol) oral contraceptives (COC) as part of CONRAD 114 study. Vaginal biopsies were taken at baseline and after treatments. RNA extracted from biopsies was hybridized to Affymetrix U133 Plus 2 arrays. Microarray data were processed using BRB-arrays tools. Genes with statistically different expression (p< 0.001) between baseline and treatment and fold change difference ≥ 2 were considered differentially expressed. Functional analysis was done using Ingenuity Pathway Analysis and published data.
Results: Microarray and functional analyses revealed that HCs did not cause significant changes in inflammation-related genes in the vaginal mucosa. The most striking DMPA effect was a strong downregulation of genes involved in maintenance of epithelial barrier function including, among others, genes belonging to the epidermal differentiation complex: repetin (RPTN), filaggrin (FLG), and late cornified envelope 3D (LCE3D). A similar pattern has previously been observed under mucosal inflammatory conditions. In contrast, no change in the expression of these genes was observed in COC users. Protein expression (immunohistochemistry) confirmed these findings.
Conclusions: A significant decrease in expression of genes related to epithelial barrier function as a result of use of injectable DMPA or vaginal inflammation may lead to epithelial barrier compromise, possibly increasing virus penetration and recruitment of HIV target cells to the cervicovaginal mucosa.
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