HIV-1 proteins gp120 and tat induce the epithelial–mesenchymal transition in oral and genital mucosal epithelial cells

Autoři: Kathy Lien aff001;  Wasima Mayer aff001;  Rossana Herrera aff001;  Kristina Rosbe aff002;  Sharof M. Tugizov aff001
Působiště autorů: Department of Medicine, University of California–San Francisco, San Francisco, CA, United States of America aff001;  Department of Otolaryngology, University of California–San Francisco, San Francisco, CA, United States of America aff002;  Department of Obstetrics, Gynecology & Reproductive Sciences, University of California–San Francisco, San Francisco, CA, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


The oral, cervical, and genital mucosa, covered by stratified squamous epithelia with polarized organization and strong tight and adherens junctions, play a critical role in preventing transmission of viral pathogens, including human immunodeficiency virus (HIV). HIV-1 interaction with mucosal epithelial cells may depolarize epithelia and disrupt their tight and adherens junctions; however, the molecular mechanism of HIV-induced epithelial disruption has not been completely understood. We showed that prolonged interaction of cell-free HIV-1 virions, and viral envelope and transactivator proteins gp120 and tat, respectively, with tonsil, cervical, and foreskin epithelial cells induces an epithelial–mesenchymal transition (EMT). EMT is an epigenetic process leading to the disruption of mucosal epithelia and allowing the paracellular spread of viral and other pathogens. Interaction of cell-free virions and gp120 and tat proteins with epithelial cells substantially reduced E-cadherin expression and activated vimentin and N-cadherin expression, which are well-known mesenchymal markers. HIV gp120- and tat-induced EMT was mediated by SMAD2 phosphorylation and activation of transcription factors Slug, Snail, Twist1 and ZEB1. Activation of TGF-β and MAPK signaling by gp120, tat, and cell-free HIV virions revealed the critical roles of these signaling pathways in EMT induction. gp120- and tat-induced EMT cells were highly migratory via collagen-coated membranes, which is one of the main features of mesenchymal cells. Inhibitors of TGF-β1 and MAPK signaling reduced HIV-induced EMT, suggesting that inactivation of these signaling pathways may restore the normal barrier function of mucosal epithelia.

Klíčová slova:

Epithelial cells – HIV-1 – Keratinocytes – MAPK signaling cascades – TGF-beta signaling cascade – Tonsils – Vimentin


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2019 Číslo 12
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