Matrix Metalloproteinases Expressed in Response to Bacterial Vaginosis Disrupt the Endocervical Epithelium, Increasing Transmigration of HIV

Abstract

Bacterial vaginosis (BV), a disorder of the female reproductive tract (FRT) in which a healthy Lactobacillus-dominant microflora is replaced by BV-associated bacteria (BVAB), can significantly increase the incidence of human immunodeficiency virus (HIV) acquisition. Discerning the effect of BV on the mucosal epithelium of the FRT may yield novel preventatives and therapeutics for HIV infection. Here, we investigated barrier dysfunction of the endocervix by host-derived factors, secreted in response to BV, as a potential cause of HIV infection. Using a polarized endocervical cell culture system, we determined that conditioned media (CM) from endocervical cells cocultured with BVAB (endocervical+BVAB CM), as well as cervicovaginal fluid (CVF) from women with BV, disrupted epithelial polarization. We assessed host matrix metalloproteinases (MMPs) as the BV-associated secreted factors which disrupt the endocervical epithelium. MMPs were overexpressed in endocervical+BVAB CM and CVF from women with BV and were capable of disrupting endocervical epithelial polarization. When we cocultured polarized endocervical cells with HIV-1-infected lymphocyte-derived cells, we discovered endocervical+BVAB CM and MMPs significantly increased the transmigration of virus through the epithelium, and treatment with an MMP inhibitor decreased these effects. When we examined the effect of CVF on HIV-1 transmigration through endocervical epithelium, we demonstrated that CVF samples with greater concentrations of BV-associated MMPs increased viral transmigration. Our results suggest MMPs increase HIV-1 infection by disrupting the endocervical epithelium, permitting transmigration of virus through the epithelium to infect underlying target cells.

Transient association between semen exposure and biomarkers of genital inflammation in South African women at risk of HIV infection

“…MMPs and their regulators, TIMPs are involved in the remodelling of the extracellular matrix. Increased expression of MMPs is associated with elevated genital cytokines, epithelial barrier disruption and HIV transmigration [5,31]. Therefore, we compared cervicovaginal YcDNA concentrations with MMP/TIMP concentrations at baseline (n = 40).…”

Semen: A modulator of female genital tract inflammation and a vector for HIV‐1 transmission

“…Specific BV‐associated bacteria ( Prevotella , G. vaginalis , Sneathia , Parvimonas and Gemella ) have been significantly associated with genital inflammation and an increased risk of HIV acquisition in women 4,5,7,101 . These microbes contribute to inflammation through activation of the nuclear factor kappa B (NF‐κB) pathway, increasing genital cytokines, immune cell recruitment, reduced epithelial barrier integrity, and impaired wound healing 4,6,49,102 . These studies highlight the role of genital inflammation in susceptibility to HIV infection in women.…”

“…Arnold et al 3 also demonstrated that increased concentrations of matrix metalloproteinases (MMP)‐8 and 9, proteins involved in the remodelling of the extracellular matrix, are associated with raised cytokine biomarkers of inflammation. Elevated levels of MMPs in vaginal fluid from women with BV were also shown to disrupt endocervical epithelial polarisation and increase HIV transmigration through the endocervical epithelium 6 . Additionally, a study conducted in mice demonstrated that tissue inflammation induced remodelling of the extracellular matrix and altered CD4+ T cell motility 95 .…”

“…Semen‐derived IL‐1β may also increase vaginal epithelium tight junction permeability through the activation of the NF‐κβ pathway 200 . Elevated levels of MMPs have also been linked to reduced mucosal barrier integrity, increased cervicovaginal cytokine production, immune cell recruitment at the vaginal mucosa and increased HIV transmigration 3,6 . We have recently demonstrated that semen exposure is associated with increased concentrations of MMP‐2 and their inhibitors in vaginal specimens 165 .…”

“…Genital inflammation, defined by elevated pro‐inflammatory and chemotactic cytokines, has also been linked to a three‐fold greater risk of acquiring HIV in women 2 . Additionally, microbial dysbiosis contributes to inflammation through increased cytokine production, mucosal barrier disruption and immune cell recruitment at the female genital tract (FGT) 4‐7 . These studies emphasise the role of genital inflammation in HIV acquisition in women and highlight the need to determine factors that contribute to genital inflammation and then limit their relative impact on HIV risk.…”