The relationship between sex hormones, the vaginal microbiome and immunity in HIV-1 susceptibility in women

Abstract

The role of sex hormones in regulating immune responses in the female genital tract has been recognized for decades. More recently, it has become increasingly clear that sex hormones regulate susceptibility to sexually transmitted infections through direct and indirect mechanisms involving inflammation and immune responses. The reproductive cycle can influence simian/human immunodeficiency virus (SHIV) infections in primates and HIV-1 infection in ex vivo cervical tissues from women. Exogenous hormones, such as those found in hormonal contraceptives, have come under intense scrutiny because of the increased susceptibility to sexually transmitted infections seen in women using medroxyprogesterone acetate, a synthetic progestin-based contraceptive. Recent meta-analyses concluded that medroxyprogesterone acetate enhanced HIV-1 susceptibility in women by 40%. In contrast, estradiol-containing hormonal contraceptives were not associated with increased susceptibility and some studies reported a protective effect of estrogen on HIV/SIV infection, although the underlying mechanisms remain incompletely understood. Recent studies describe a key role for the vaginal microbiota in determining susceptibility to sexually transmitted infections, including HIV-1. While Lactobacillus spp.-dominated vaginal microbiota is associated with decreased susceptibility, complex microbiota, such as those seen in bacterial vaginosis, correlates with increased susceptibility to HIV-1. Interestingly, sex hormones are inherently linked to microbiota regulation in the vaginal tract. Estrogen has been postulated to play a key role in establishing a Lactobacillus-dominated microenvironment, whereas medroxyprogesterone acetate is linked to hypo-estrogenic effects. The aim of this Review is to contribute to a better understanding of the sex-hormone-microbiome-immunity axis, which can provide key information on the determinants of HIV-1 susceptibility in the female genital tract and, consequently, inform HIV-1 prevention strategies.

Keywords: DMPA; Inflammation; T cells; Vaginal microbiota.

Fig. 1.

Anatomy and immunological components of the female genital tract. The female genital tract (FGT) can be separated into the upper (ovary, fallopian tube, uterus/endometrium and endocervix) and lower (ectocervix and vagina) tract. The vaginal epithelium has many innate immune protection mechanisms, such as tight junctions, antimicrobial peptides (AMPs) and mucus, in order to neutralize, trap and prevent entry of potential pathogens. The vaginal lumen is colonized by commensal bacteria, mainly lactobacilli, which help to maintain a low pH. Furthermore, immune cells such as γδ T cells, dendritic cells (DCs) and macrophages are present beneath and between the vaginal epithelial cell layer to survey the local environment for danger. The abrupt transition from keratinized squamous epithelial cells of the ectocervix to single columnar epithelial cells of the endocervix represents the transformation zone; this site has an abundance of HIV-1 target cells and has been proposed to be one of the major sites for infections. The presence of lymphoid aggregates in the endometrial tissue suggests that this is an inductive site for cell-mediated immunity. Lymphoid aggregates found beneath the endometrium are composed of B cells in the inner core surrounded by CD8⁺ CD4⁻ T cells and an outer layer of macrophages. A scatter of CD56⁺ natural killer (NK) cells and CD4⁺ T cells could be found in between lymphoid aggregates. It was originally believed that the upper FGT was sterile; however, like the vaginal tract, the upper FGT is colonized by bacteria, including lactobacilli. Figure modified and reprinted with permission from Nguyen et al. (2014). TLR, Toll-like receptor.

Fig. 2.

Changes in lower female genital tract immunity and HIV-1 susceptibility under endogenous and exogenous sex hormones. The endogenous levels of female sex hormones (estradiol and progesterone) vary throughout the 28-day menstrual cycle in women. Estradiol dominates the follicular phase and reaches peak levels just prior to ovulation, which occurs around day 14. Post-ovulation, estradiol levels decline as progesterone levels rise towards the mid-luteal phase. The progestin-based injectable contraceptive depot-medroxyprogesterone acetate (DMPA) is administered every 3 months. Levels of this progestin, a synthetic progesterone, are highest in serum within the first 20 days of administration. Women on DMPA have consistently lower estradiol levels than normally cycling women (Hapgood et al., 2018). A summary of the putative effects of hormones and hormonal contraceptives on female genital tract (FGT) immunity as presented in this Review are summarized as shown. Overall, while estradiol appears to promote factors related to decreased HIV-1 susceptibility, alterations in immunity during periods of high progesterone or DMPA use are associated with increased HIV-1 susceptibility. DCs, dendritic cells; Ig, immunoglobulin; Th2, T-helper type 2 cells; Th17, T-helper 17 cells.

Fig. 3.

Factors affecting susceptibility to HIV-1 in women. There are many factors associated with an increased risk of HIV-1 in women, including disruption of the vaginal barrier, concurrent STIs, the sex hormones, hormonal contraceptives and the vaginal microbiota (VMB). However, the establishment of HIV-1 infection is multifactorial and likely involves mechanisms that remain to be elucidated. A word cloud was created using wordclouds.com to depict factors associated with increasing susceptibility to HIV-1 in women. The size of the text is proportional to the number of publications returned in PubMed (March 2018) when searching for HIV-1 and the corresponding factor. Factors returning 25-99 hits (i.e. hormonal contraceptives) are listed in the smallest font, followed by factors returning 100-499 hits (i.e. sex hormones), 500-999 hits (i.e. target cells), and the largest font represents factors with more than 1000 hits (i.e. inflammation).

Fig. 4.

The sex-hormone–microbiome–immunity axis and HIV-1 susceptibility in women. An illustration depicting how the hormonal milieu of the lower female genital tract (FGT) might impact susceptibility to HIV-1. (A) Anatomy of the FGT. (B,C) Immunity and the microbiota in the lower FGT. (B) When estradiol is dominant, glycogen, a glucose polysaccharide that is correlated with enhanced vaginal lactobacilli, is abundant and adequately sustains the colonization of the vaginal mucosa by Lactobacillus species, via unknown mechanisms. Several studies have reported that a vaginal microbiota (VMB) dominated by species of lactobacilli is protective against HIV-1, perhaps a result of dampened innate inflammation and a reduction in activated T cells. In a microenvironment influenced by estradiol, epidemiological and experimental studies collectively suggest that susceptibility to HIV-1 appears to be hampered (Hapgood et al., 2018). (C) Conversely, when DMPA (MPA is the active ingredient in DMPA) is dominant, endogenous estradiol is suppressed due to the hypo-estrogenic effect of DMPA. As a result, glycogen deposition in the vaginal epithelium may be minimized, depleting one of the important nutrients that may sustain the protective vaginal lactobacilli. Given the depletion in nutrients, lactobacilli are not as numerous as when they are under the influence of estradiol, and a more diverse array of bacteria is subsequently supported in the VMB. In turn, the diverse bacteria might induce innate immunity in the FGT, upregulating cytokines, inflammation and activated T cells. Given that activated T cells are a major target of HIV-1, this type of environment would ultimately enhance susceptibility to HIV-1 in women. At present, it is unclear whether this proposed mechanism is a direct result of exposure to DMPA or an indirect result of hypo-estrogenism. AMPs, antimicrobial peptides; DMPA, depot-medroxyprogesterone acetate; HIV-1, human immunodeficiency virus type 1; MPA, medroxyprogesterone acetate.