Abstract
ABSTRACTThe 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.
Highlights
Clinical and experimental evidence indicates that many sexually transmitted infections (STIs) are more prevalent in women than men (Kaushic et al, 2011)
This is an important and timely topic, given that approximately 40% of human immunodeficiency virus (HIV)-1 infections occur in the female genital tract (FGT) and that women using the progestin-based injectable contraceptive depot-medroxyprogesterone acetate (DMPA) are 40% more likely to acquire HIV-1 than women not using hormonal contraceptives (Polis et al, 2016)
We focus on the effect of endogenous and exogenous hormones in modulating key target cell populations, and HIV-1 susceptibility, in the lower FGT
Summary
Clinical and experimental evidence indicates that many sexually transmitted infections (STIs) are more prevalent in women than men (Kaushic et al, 2011). The biological factors that could influence the outcome of pathogen exposure in the FGT include its large surface area, the alterations in physiology of reproductive tract tissues during different phases of the menstrual cycle, the influence of sex hormones on mucosal immune defense, the use of hormonal contraceptives and the effect of the indigenous microbiota (see Box 1 for a glossary of terms). In this Review, we highlight the mechanisms by which sex steroid hormones, including hormonal contraceptives, might impact the risk of HIV-1 susceptibility in women. The relevance of this area to public health is emphasized by the fact that more than 8 million women in subSaharan Africa, where HIV-1 is endemic, use DMPA as their main form of contraception (Ross and Agwanda, 2012)
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