Understanding Factors That Modulate HIV Infection at the Female Genital Tract Mucosae for the Rationale Design of Microbicides

Women are now becoming the pivot of the epidemiological spread of HIV infection worldwide, especially in developing countries. Therefore, research to develop an efficient microbicide is now a priority for the prevention of HIV-1 acquisition in exposed women. However, recent disappointing failures in microbicide clinical trials revealed major gaps in basic and applied knowledge that hinder the development of effective microbicide formulations. Indeed, the inhibitory power of microbicide molecules may be affected by several physiological and immunological factors present in male and female genital tracts. Furthermore, mucosal crossing of HIV-1 to increase the ability to reach the submucosal target cells (macrophages, lymphocytes, and dendritic cells) may be modulated by supraepithelial factors such as seminal complement components (opsonized HIV-1), by epithelial factors released in the submucosal microenvironment such as antimicrobial soluble factors, cytokines, and chemokines, and by potent intraepithelial and submucosal innate immunity. The design of vaginal microbicide formulations should take into account an understanding of the intimate mechanisms involved in the crossing of HIV through the female genital mucosae, in the context of a mixture of both male and female genital fluids.