Role of Sex Hormones in Regulating Innate Immune Protection against HIV in the Human Female Reproductive Tract

Immune protection in the female reproductive tract (FRT) has evolved to meet the challenges of sexually transmitted bacterial and viral pathogens, allogeneic spermatozoa, and an immunologically distinct semi-allogeneic fetus. Throughout the FRT, the innate immune system is essential for the recognition and initial response to incoming pathogens. Key mediators of innate immune protection examined in this review include epithelial cells, stromal fibroblasts, macrophages, DC, and neutrophils from the Fallopian tubes, uterus, cervix and vagina. These innate immune cells respond to pathogens resulting in the secretion of cytokines, chemokines, antimicrobials, and production of intracellular proteins that protect, activate and recruit both innate and adaptive immune cells. Human immunodeficiency virus (HIV) infection can occur throughout the FRT, including the ovary, and is modulated by multiple factors including age of the individual, epithelial barrier integrity, composition of the vaginal microbiome, and hormonal status. Alterations in immune function due to hormonal changes that optimize conditions for successful fertilization create a hypothesized “window of vulnerability” that lasts from ovulation into the secretory stage of the menstrual cycle. The goal of this review is to summarize the multiple levels of protection against HIV infection in the FRT and thereby providing a foundation for the design of vaccines for protection against sexually-transmitted infections (STI) including HIV.