Effects of depot-medroxyprogesterone acetate on the immune microenvironment of the human cervix and endometrium: implications for HIV susceptibility

Abstract

Depot-medroxyprogesterone acetate is a commonly used injectable contraceptive that has been associated with an increased risk of HIV acquisition. This study compares effects of depot-medroxyprogesterone acetate on immune parameters from several reproductive tract compartments relevant to HIV-1 susceptibility in upper reproductive tract samples from 15 depot-medroxyprogesterone acetate users and 27 women not on hormonal contraceptives. Compared to samples from unexposed women in the mid-luteal phase, depot-medroxyprogesterone acetate use was associated with: increased endocervical concentrations of MCP1 and IFNalpha2; decreased endocervical concentrations of IL1beta and IL6; increased proportions of endometrial CD4+ and CD8+ cells expressing the activation marker HLADR; increased density of endometrial macrophages; and decreased density of endometrial regulatory T-cells. Unlike previous reports with samples from the vagina, we did not observe increased expression of the HIV co-receptor CCR5 on CD4+ T-cells in the endocervix or endometrium. Our results indicate important differences in anatomic compartments regarding mechanisms by which depot-medroxyprogesterone acetate could be associated with increased risk of HIV acquisition, including increased recruitment of macrophages to the endometrium, decreased levels of pro-inflammatory cytokines in the endocervix possibly leading to enhanced susceptibility to viral infection, and activation of endometrial T-cells.

Medroxyprogesterone acetate‐treated human, primary endometrial epithelial cells reveal unique gene expression signature linked to innate immunity and HIV‐1 susceptibility

“…Interestingly, a recent transcriptomic study revealed that women using the progestin‐based hormonal contraceptives DMPA or levonorgestrel intrauterine system (LNG‐IUS) have increased expression of genes involved in chemotaxis, attachment, and inflammation from whole tissue samples from the endometrium . It was also determined that women treated with DMPA have higher numbers of endometrial macrophages which have been shown to be the primary target for HIV‐1 infection in the endometrium . Thus, our study and others suggest that DMPA influences the numbers of HIV‐1 target cells through chemotactic recruitment.…”

Progestin‐based contraception regimens modulate expression of putative HIV risk factors in the vaginal epithelium of pig‐tailed Macaques

“…[3][4][5][6][7] An ongoing randomized study called the ECHO (Evidence for In our prior study, we showed that altered expression of putative HIV/SIV factors during the luteal phase of the menstrual cycle could contribute to greater risk of vaginal acquisition during this phase. [3][4][5][6][7] An ongoing randomized study called the ECHO (Evidence for In our prior study, we showed that altered expression of putative HIV/SIV factors during the luteal phase of the menstrual cycle could contribute to greater risk of vaginal acquisition during this phase.…”

“…Past studies have expressed more concern with use of DMPA than with LNG-based contraception with respect to HIV acquisition risk. [3][4][5][6][7] An ongoing randomized study called the ECHO (Evidence for IL-10, a multifunctional cytokine with both proinflammatory and immunoregulatory properties, is known to block viral clearance and enhance HIV pathogenesis. 24 Previous reports have demonstrated that viruses specifically exploit IL-10 to evade the host immune system.…”

“…There is significant debate on whether DMPA use has a causal link with increased risk of acquiring HIV. [3][4][5][6][7] However, other popular progestin-based forms of birth control, including estrogen-containing combined oral contraceptives (COCs), do not seem to be associated with increased HIV risk. 6 The luteal phase of the menstrual cycle, which exhibits naturally high-progesterone levels, is also known to present a window of higher susceptibility to simian-human immunodeficiency virus (SHIV) infection in macaques.…”

Depot Medroxyprogesterone Acetate Administration Alters Immune Markers for HIV Preference and Increases Susceptibility of Peripheral CD4+ T Cells to HIV Infection

“…Depo-Provera users have higher levels of activated endometrial T cells along with a higher percentage of endometrial CD4 + naïve and CM subsets compared to women not using hormonal contraceptives, although there is no difference in their TEM subsets (47). We observed a similar increasing tread of naïve and CM CD4 + T cells subsets in response to Depo-Provera, especially in black patients, indicating changes in CD4 + T cell subsets by Depo-Provera may not be compartmentalized.…”