The Role of Sex Hormones and the Tissue Environment in Immune Protection Against HIV in the Female Reproductive Tract

Abstract

Despite extensive studies of the mucosal immune system in the female reproductive tract (FRT) and its regulation by sex hormones, relatively little attention has been paid to the tissue environment in the FRT that regulates immune cell function. Consisting of secretions from epithelial cells, stromal fibroblasts and immune cells in tissues from the upper (Fallopian tubes, uterus and endocervix) and lower (ectocervix and vagina) tracts, each tissue compartment is unique and precisely regulates immune cells to optimize conditions for successful pregnancy and protection against sexually transmitted diseases including HIV. Our goal in this Review is to focus on the mucosal (tissue) environment in the upper and lower FRT. Specifically, this review will identify the contributions of epithelial cells and fibroblasts to the tissue environment and examine the impact of this environment on HIV-target cells. Much remains to be learned about the complex interactions with the tissue environment at different sites in the FRT and the ways in which they are regulated by sex hormones and chemical contraceptives. Awareness of the involvement of the tissue environment in determining immune cell function and HIV acquisition is crucial for the understanding the mechanisms that lead to HIV prevention, acquisition and the development of new therapeutic modalities of immune protection.

Mucosal B Cells Are Associated with Delayed SIV Acquisition in Vaccinated Female but Not Male Rhesus Macaques Following SIVmac251 Rectal Challenge

“…Female sex hormone changes throughout the menstrual cycle impact susceptibility to vaginal HIV infection by affecting all arms of the immune system. A “window of vulnerability” in the late secretory phase of the cycle during which risk of sexually transmitted infections is highest was postulated [ 58 ], and corroborated by the demonstrations during the secretory phase of more frequent vaginal SHIV transmission to macaques [ 59 ] and better ex vivo HIV infection of human cervical explants [ 60 ]. We did not synchronize our female macaques, as rectal challenges were planned.…”

Analysis of the collagen fibers on autopsied patients’ uterus with the Acquired Immunodeficiency Syndrome

“…19 However, studies show that in chronic HIV infection, the epithelial cells, fibroblasts and the immune cells that reside in the female reproductive tract tissues contribute to the pool of cytokines, chemokines and growth factors present in the sexual hormones tissue environment, estradiol and progesterone. 20 Since fibroblasts respond to several immunological mediators, the immune alterations in patients with HIV could affect their functions, leading to modifications in the responses of producing and/or reducing collagen fibers. 21 In this present study, a significantly higher percentage of collagen fibers was detected in the uterine body of patients with Aids when compared to the group without Aids.…”

“…This apparent paradox in relation to the HIV infection is dependent on many factors, including the quantity of the epithelial factors secretion is in the female reproductive tract, the presence of co-infecting pathogens, the presence of proteolytic enzymes, the sexual hormone balance, the activation of cells status, the interaction of other secreted factors by other cells as well as the epithelial cells and the present types of immune cells. 20 In the uterus during the proliferative phase, the aggregated lymphoid consist of cell groups CD4+ T or CD8+ discreet (300 cells). During the secreting phase,the aggregated lymphoid increased to 3,000-4,000 cells.…”

“…24 These findings led us to propose a hypothesis of a "vulnerability window" (starting with ovulation and lasting between 7-10 days until the secreting phase of the cycle) what suggests that endocrine alterations modulate the immune protection in a way that increases the probability of the HIV infection and sexually transmitted infections (STI). 24,20 Therefore, this percentage of increased collagen fibers in the uterine body in the group with Aids may be related to chronic HIV infection, since the induction of a cellular immune response characterized by the predominance of cytotoxic T lymphocytes, despite having a protective effect against HIV-1 genital infection, 25 are not sufficient to control viremia in patients with chronic infection. 26 Once deposited in the vagina, the sperm moves rapidly into the cervix, uterine body, Fallopian tubes and ovaries, potentially leading to an exposure over a large and phenotypically diverse mucosal surface.…”

Pharmacology of Antiretrovirals in the Female Genital Tract for HIV Prevention

“…It has been well established that estradiol and progesterone heavily regulate immune function within the female genital tract . In addition, these hormones have been shown to mediate enzymes and transporters, which could lead to altered pharmacology during times of high or low hormone exposure.…”