New approaches to making the microenvironment of the female reproductive tract hostile to HIV

Abstract

The studies presented in this review explore three distinct areas with potential for inhibiting HIV infection in women. Based on emerging information from the physiology, endocrinology and immunology of the female reproductive tract (FRT), we propose unique 'works in progress' for protecting women from HIV. Various aspects of FRT immunity are suppressed by estradiol during the menstrual cycle, making women more susceptible to HIV infection. By engineering commensal Lactobacillus to secrete the anti-HIV molecule Elafin as estradiol levels increase, women could be protected from HIV infection. Selective estrogen response modifiers enhance barrier integrity and enhance secretion of protective anti-HIV molecules. Finally, understanding the interactions and regulation of FRT endogenous antimicrobials, proteases, antiproteases, etc., all of which are under hormonal control, will open new avenues to therapeutic manipulation of the FRT mucosal microenvironment. By seeking new alternatives to preventing HIV infection in women, we may finally disrupt the HIV pandemic.

Fig. 1

Elafin suppresses HIV infection. Supernates (20-fold dilution) from 24-hr cultures of L. jensenii, which contained either no vector, the empty APU vector or APU encoding for engineered Elafin, were incubated with the IIIB HIV virus for 1 hr. The mixture was transferred to TZM-bl cells and cultured for an additional 48 hr. Viability and beta galactosidase activity were determined. Increased beta galactosidase activity expressed as relative light units (RLU) is a measure of HIV infection. Data are presented as mean ± SD of replicate samples.

Fig. 2

CCL20 is secreted from isolated uterine epithelial cells in vitro following 24-hr stimulation with 10⁻⁷ M estradiol, 10⁻⁷ M ICI 182780, 10⁻⁷ M Tamoxifen, 10⁻⁷ M Y134 or 10⁻⁷ M PHTPP. *P < 0.05, **P < 0.01, ***P < 0.001, one-way ANOVA, Bonferroni’s post hoc.

Fig. 3

An example of antimicrobial complexity in the FRT: regulation of anti-HIV molecules by cathepsin proteases. Other regulators of innate immune factors in the FRT include proteases, antiproteases, Kallikreins, matrix metalloproteases, etc. The majority of proteases and their substrates are regulated by sex hormones. The antimicrobials SLPI and Elafin are protease inhibitors and anti-HIV factors.