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

J W Critchfield,U Shanmugasundaram,B L Shacklett,J F Hilton,D Seidman,R M Greenblatt,K K Smith-McCune,S Averbach,L C Giudice

doi:10.1038/mi.2016.121

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 upper reproductive tract compartments relevant to HIV-1 susceptibility in repetitive samples from 15 depot-medroxyprogesterone acetate users and 27 women not on hormonal contraceptives. Compared with 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.

Highlights

Forty-one million women worldwide use injectable hormonal contraception, over a quarter of whom live in regions of Africa where the overlap of injectable method use and HIV prevalence is striking.[1,2] With limited access to alternate contraceptive methods and antiretroviral therapy, many of these areas have high maternal and HIV-related mortality.[2]
Effects of depot-medroxyprogesterone acetate (DMPA) on chemokines, cytokine and innate immune factors in the endocervical canal To determine whether DMPA altered the immune milieu of the endocervix, we studied age-adjusted concentrations of 13 proteins in endocervical fluid extracted onto absorbant wicks, contributed by 15 DMPA users and 24 Controls (Figure 1)
CD4 þ CCR5 þ T cells are major targets for HIV infection; their presence in the reproductive tract is an important surrogate for HIV susceptibility

Summary

Introduction

Forty-one million women worldwide use injectable hormonal contraception, over a quarter of whom live in regions of Africa where the overlap of injectable method use and HIV prevalence is striking.[1,2] With limited access to alternate contraceptive methods and antiretroviral therapy, many of these areas have high maternal and HIV-related mortality.[2]. Two recent meta-analyses report that women using DMPA face a 40–50% greater risk of acquiring HIV.[1,3]. The World Health Organization’s medical eligibility criteria for DMPA remains unchanged since 2012,4 recent publications question these recommendations.[5]. DMPA may increase HIV susceptibility via a variety of mechanisms. Elevated progestin levels have been associated with: increased secretion of inflammatory mediators that recruit or activate immune target cells and/or facilitate HIV replication;[6] decreased secretion of antimicrobial peptides that contribute to host defense;[7,8] increased co-receptor expression rendering cells more susceptible to HIV;[6,9] thinning of the epithelial barrier;[10] changes in the vaginal microbiome;[10,11] increased genital herpes shedding;[12,13] increased risk of herpes

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