The Role of Estradiol and Progesterone in Mucosal HIV-1 Infection, Transmission and Pathogenesis

Heterosexual transmission of the human immunodeficiency virus type-1 (HIV-1) to women occurs after exposure of the mucosal surfaces of the female reproductive tract (FRT) to cell-free virus or to HIV-1 infected cells present in the seminal fluid of an infected male partner. However, exposure to virus at this site does not always result in transmission of HIV-1, indicating that the local microenvironment in the FRT at the time of viral exposure may influence a woman's susceptibility to infection. Cleary, the sex steroid hormones, estradiol and progesterone, play an important role in the FRT. Although the primary function of these hormones is to regulate the reproductive status of a woman, they also exert profound effects on the subsets of immune cells in the FRT as well as on their phenotype and functional activity. In addition, estradiol and progesterone regulate the local cytokine and chemokine milieu by influencing the activation state of immune cells. Fluctuations in estradiol and progesterone levels in the FRT regulate expression of HIV-1 receptors CD4 and galactosyl ceramide (Gal-Cer), as well as HIV-1 co-receptors CCR5 and CXCR4. Moreover, these hormones control the development of leukocyte aggregates in the FRT that contain T cells and macrophages, resulting in foci of potential target cells for HIV-1 infection. Estradiol has also been shown to enhance HIV-1 transcription from infected cells, thereby increasing levels of viral shedding from the genital tract. In sum, these steroid hormones serve to alter a woman's susceptibility to HIV-1 infection after exposure to virus in the genital tract.