The biological mechanisms associated with Depo-Provera and HIV-1 risk acquisition in women.

Abstract

Thirty-six years after the first identification of AIDS, the spread of its aetiological agents continues unabated, human immunodeficiency virus 1 (HIV-1) in particular. About 40% of HIV-1 infections have been reported to initiate in the female reproductive tract (FRT). However, the biological mechanisms through which these infections are spread are poorly understood hence there is now a major concern in women who use injectable hormonal contraceptives, particularly medroxyprogesterone acetate (MPA) administered as depot medroxyprogesterone acetate (DMPA) or Depo-Provera and an increase of HIV-1 risk acquisition. As per literature, the glucocorticoid receptor (GR) and progesterone receptor (PR) are the main targets for Depo-Provera in the FRT. Therefore, in this study we performed molecular dynamic (MD) simulation on both the GR and the PR systems in relation to DMPA as a way of validating their docking poses and binding energy trends. We also investigated the nature of their overall interaction themes using post-dynamic analysis and most importantly, we postulated possible biological mechanisms in which DMPA may act via the GR and the PR in association with increased risk of HIV-1 infection in women. Our findings revealed that, the effect of DMPA binding to both the GR and the PR could have a great impact on increased risk of HIV-1 infection in women. The reason being that when these receptors are activated by an agonist DMPA, they interact with a few residues in the ligand binding domain (LBD) which could affect the stability state of these receptors. They also interact with NFϰB transcription factor as well as the p300 coactivator in the nucleus to cause transactivation in the ectocervical (Ect1/E6E7) epithelial cell line of the FRT, in turn, increasing mRNA and protein secretion levels of proinflammatory cytokines.