Sex steroid hormones, hormonal contraception, and the immunobiology of human immunodeficiency virus-1 infection

Abstract

Worldwide, an increasing number of women use oral or injectable hormonal contraceptives. However, inadequate information is available to aid women and health care professionals in weighing the potential risks of hormonal contraceptive use in individuals living with HIV-1 or at high risk of infection. Numerous epidemiological studies and challenge studies in a rhesus macaque model suggest that progesterone-based contraceptives increase the risk of HIV-1 infection in humans and simian immunodeficiency virus (SIV) infection in macaques, accelerate disease progression, and increase viral shedding in the genital tract. However, because several other studies in humans have not observed any effect of exogenously administered progesterone on HIV-1 acquisition and disease progression, the issue continues to be a topic of intense research and ongoing discussion. In contrast to progesterone, systemic or intravaginal treatment with estrogen efficiently protects female rhesus macaques against the transmission of SIV, likely by enhancing the natural protective properties of the lower genital tract mucosal tissue. Although the molecular and cellular mechanisms underlying the effect of sex steroid hormones on HIV-1 and SIV acquisition and disease progression are not well understood, progesterone and estrogen are known to regulate a number of immune mechanisms that may exert an effect on retroviral infection. This review summarizes current knowledge of the effects of various types of sex steroid hormones on immune processes involved in the biology of HIV-1 infection.

Figure 1

Potential effects of steroid hormones on the vaginal mucosal tissue. A, Topical or systemic treatment with estrogen results in a thickening of the vaginal epithelial layer in ovariectomized rhesus macaques. Increased thickness of mucosal epithelium may interfere with the access of the virus to target cell populations including LCs, CD4⁺ T cells, and macrophages in the epithelial and subepithelial layers. Estrogen decreases the frequency of LCs in the vaginal epithelium and lowers cervicovaginal pH, making it hostile to the virus. B, In contrast, thinner epithelial layer in progesterone-treated female macaques allows easier access of the virus to LCs and other target cells. The effect of progesterone treatment on epithelial thickness appears to be less profound in women compared with female macaques. According to some studies, progesterone treatment increases the frequency of LCs in the epithelial layer and induces changes in the vaginal microbiota, namely decreased colonization with H₂O₂-producing Lactobacillus, resulting in bacterial vaginosis. Use of progesterone-based contraceptives is associated with increased acquisition of cervical candidiasis and chlamydial and gonococcal infections in women. These factors may enhance the risk of HIV-1 acquisition.

Figure 2

Hormonal cycle and regulation of immune processes in the female genital tract. Sex steroid hormones exert a significant effect on immune processes in the female genital tract mucosa, including the activity of CTLs, B cells, frequency and antigen-presenting activity of LCs and other mechanisms.