46. HIV-induced epithelial–mesenchymal transition in mucosal epithelium facilitates HPV paracellular penetration

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Background The incidence of human papillomavirus (HPV)-associated epithelial lesions in HIV-infected individuals is substantially higher than in HIV-negative individuals. HIV may increase the risk of mucosal HPV infection by induction of an epithelial–mesenchymal transition (EMT) phenotype that leads to reduced epithelial barrier functions. Methods: To model the effect of EMT on HPV entry, we used oral epithelial biopsies, and oral and anal keratinocytes from HIV-infected and HIV-uninfected individuals. EMT was defined as loss of adherens and tight junctions, and induction of vimentin expression. To study epithelial HPV entry we used HPV-16 pseudovirions (PsVs) containing a plasmid expressing red fluorescent protein (RFP). PsV penetration was evaluated using confocal microscopy to detect RFP-generated fluorescence. Results: Compared with oral epithelia from HIV-uninfected individuals, oral epithelia from HIV-infected individuals had reduced adherens and tight junctions and expressed vimentin. Keratinocytes isolated from oral and anal tissues of HIV-infected individuals also showed loss of E-cadherin and induction of vimentin expression. Exposure of oral epithelial cells from HIV-uninfected individuals to HIV and HIV tat, gp120, and nef proteins induced EMT with reduced cell junctions and epithelial polarity, and allowed paracellular passage of HPV-16 PsV. Oral mucosal epithelial tissues treated with HIV tat and gp120 also lost tight junctions and allowed PsV paracellular penetration, leading to PsV entry into basal/parabasal cells. Conclusions: HIV-associated EMT in oral epithelia, and oral and anal keratinocytes leads to impaired barrier function. This facilitates entry of HPV/PsV into basal/parabasal cells, and may contribute to the increased incidence of HPV-associated malignancy in HIV-infected individuals.

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