Abstract
Women at high risk of HIV infection, including sex workers and those with active genital inflammation, have molecular signatures of immune activation and epithelial barrier remodeling in samples of their genital mucosa. These alterations in the local immunological milieu are likely to impact HIV susceptibility. We here analyze host genital protein signatures in HIV uninfected women, with high frequency of condom use, living in HIV-serodiscordant relationships. Cervicovaginal secretions from women living in HIV-serodiscordant relationships (n = 62) were collected at three time points over 12 months. Women living in HIV-negative seroconcordant relationships (controls, n = 25) were sampled at one time point. All study subjects were examined for demographic parameters associated with susceptibility to HIV infection. The cervicovaginal samples were analyzed using a high-throughput bead-based affinity assay. Proteins involved in epithelial barrier function and inflammation were increased in HIV-serodiscordant women. By combining several methods of analysis, a total of five proteins (CAPG, KLK10, SPRR3, elafin/PI3, CSTB) were consistently associated with this study group. Proteins analyzed using the affinity set-up were further validated by label-free tandem mass spectrometry in a partially overlapping cohort with concordant results. Women living in HIV-serodiscordant relationships thus had elevated levels of proteins involved in epithelial barrier function and inflammation despite low prevalence of sexually transmitted infections and a high frequency of safe sex practices. The identified proteins are important markers to follow during assessment of mucosal HIV susceptibility factors and a high-throughput bead-based affinity set-up could be a suitable method for such evaluation.
Highlights
An estimated 1.8 million individuals became newly infected with human immunodeficiency virus (HIV)1 in 2016 [1], and about 64% of these infections occurred in sub-Saharan Africa
In order to only include complete time series from all women in the data analysis, we excluded the additional time points from the 10 serodiscordant women. This resulted in 211 samples (62 serodiscordant women with 3 samples per woman and 25 controls with 1 sample per woman) that were subjected to biological data analysis in the initial stage
We found proteins involved in epithelial barrier integrity and inflammation at higher levels in cervicovaginal secretions (CVS) from HIV-uninfected women living in HIV-serodiscordant relationships relative to women with an HIV-seronegative partner
Summary
Collected genital samples from women in HIVserodiscordant relationships were analyzed using a highthroughput bead-based affinity assay, revealing elevated levels of proteins involved in epithelial barrier integrity and inflammation. Genital protein signature profiles including immune activation have been proposed as objective measures of mucosal safety in clinical trials (24 –26) Elucidating these protective factors will improve our understanding of natural resistance in high-risk groups such as HIV-serodiscordant couples. Bead-based affinity proteomic techniques provide an alternate approach that confers a higher-throughput assessment of individual samples [27, 28] We applied this technique to examine genital secretions in a unique cohort of HIV-serodiscordant couples from multiple time points, using samples from HIV-uninfected women in HIV-seroconcordant relationships as a control. The objectives were to characterize mucosal protein signatures of women living in HIV-serodiscordant relationships and to evaluate the feasibility of using a highthroughput bead-based affinity set-up for evaluation of protein expression in cervicovaginal secretions (CVS)
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