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.

The rodent vaginal microbiome across the estrous cycle and the effect of genital nerve electrical stimulation

“…In a similar vein, studies have shown that women with bladder issues such as urge urinary incontinence have more diverse bladder microbiomes than women without incontinence (69,70). Additionally, studies have shown that women with imbalances in Lactobacillus in their vaginal microbiome can have changes in hormones associated with cervicovaginal inflammation, which leads to changes in their vaginal immunity and HIV susceptibility (10,57,71). It is possible that the handling and stress of the study contributed to an increase in the microbiome diversity for Control animals, and that the three Treatment rats with lower rate of increase or a decrease were affected by stimulation.…”

“…This reduction of a dominating species and overall increase in the diversity of the vaginal microbiome is associated with an overall reduction in vaginal health in postmenopausal women (8). Postmenopausal women are 7.8 times more likely to have a more diverse vaginal microbiome than are premenopausal women (9), and this may be due to decreases in their concentrations of ovarian hormones (10). This suggests that hormone changes associated with menopause may have an effect on the vaginal microbiome.…”

The influence of sex on the urogenital microbiome of rhesus monkeys

“…This is supported by our finding that the observed changes in bacterial vaginal diversity in the rhesus monkeys coincide with changes in the pH, a functional measurement of the vaginal ecosystem. Understanding the causal relationships that regulate and control changes in vaginal ecosystem is a current challenge for both NHP and human microbiome studies (reviewed by ( 22 )) and warrants further investigation.…”

The Interplay Between Reproductive Tract Microbiota and Immunological System in Human Reproduction

“…In particular, estradiol has been implicated in the shift from a Lactobacillus-poor to a Lactobacillus-rich vaginal microbiota during puberty, as well as a reverse shift after menopause (86). Estrogen-induced glycogen synthesis in epithelial cells and production of glycogen-metabolites (maltose, maltotriose, α-dextrines) provides substrates for conversion to lactic acid by Lactobacilli (87)(88)(89). At reproductive age, a healthy vaginal microbiota was found to amplify the fluctuation in local immune responses in synchrony with hormonal changes during the menstrual cycle (90).…”