Abstract
Vaginal microbicides hold great promise for the prevention of viral diseases like HIV, but the failure of several microbicide candidates in clinical trials has raised important questions regarding the parameters to be evaluated to determine in vivo efficacy in humans. Clinical trials of the candidate microbicides nonoxynol-9 (N9) and cellulose sulfate revealed an increase in HIV infection, vaginal inflammation, and recruitment of HIV susceptible lymphocytes, highlighting the need to identify biomarkers that can accurately predict microbicide toxicity early in preclinical development and in human trials. We used quantitative proteomics and RT-PCR approaches in mice and rabbits to identify protein changes in vaginal fluid and tissue in response to treatment with N9 or benzalkonium chloride (BZK). We compared changes generated with N9 and BZK treatment to the changes generated in response to tenofovir gel, a candidate microbicide that holds promise as a safe and effective microbicide. Both compounds down regulated mucin 5 subtype B, and peptidoglycan recognition protein 1 in vaginal tissue; however, mucosal brush samples also showed upregulation of plasma proteins fibrinogen, plasminogen, apolipoprotein A-1, and apolipoprotein C-1, which may be a response to the erosive nature of N9 and BZK. Additional proteins down-regulated in vaginal tissue by N9 or BZK treatment include CD166 antigen, olfactomedin-4, and anterior gradient protein 2 homolog. We also observed increases in the expression of C-C chemokines CCL3, CCL5, and CCL7 in response to treatment. There was concordance in expression level changes for several of these proteins using both the mouse and rabbit models. Using a human vaginal epithelial cell line, the expression of mucin 5 subtype B and olfactomedin-4 were down-regulated in response to N9, suggesting these markers could apply to humans. These data identifies new proteins that after further validation could become part of a panel of biomarkers to effectively evaluate microbicide toxicity.
Highlights
Topical microbicides have been proposed as agents to prevent the transmission of HIV by creating chemical, biological, and/or physical barriers to infection, or by blocking or inactivating the virus at the mucosal surface where infection can occur
To identify protein changes induced by vaginal microbicide candidates with an undesirable safety profile, mice were treated with either vehicle, 8% N9, 2% benzalkonium chloride (BZK), or 1% tenofovir [32] for 10 consecutive days, with mucosal samples and tissue samples collected at day 7 and 10 for analysis by 2D LC-MS/MS, respectively
A total of 1017 proteins were identified with a false discovery rate (FDR) cutoff of 0.05
Summary
Topical microbicides have been proposed as agents to prevent the transmission of HIV by creating chemical, biological, and/or physical barriers to infection, or by blocking or inactivating the virus at the mucosal surface where infection can occur. Several candidate microbicides initially appeared promising in preclinical safety studies, they later proved to be ineffective in clinical trials [1,2,3,4,5,6,7,8,9,10,11,12,13] In some cases, they increased the risk of infection, e.g. cellulose sulfate [12]. One approach is to develop a robust series of biomarkers capable of predicting cellular and molecular changes occurring in the vaginal mucosa/epithelium during microbicide treatment Such markers could have utility both in preclinical development and, eventually, in clinical development as well
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