The CXCL12/CXCR4 Signaling Pathway: A New Susceptibility Factor in Human Papillomavirus Pathogenesis

The productive human papillomavirus (HPV) life cycle is tightly linked to the differentiation and cycling of keratinocytes. Deregulation of these processes and stimulation of cell proliferation by the action of viral oncoproteins and host cell factors underlies HPV-mediated carcinogenesis. Severe HPV infections characterize the wart, hypogammaglobulinemia, infection, and myelokathexis (WHIM) immunodeficiency syndrome, which is caused by gain-of-function mutations in the CXCR4 receptor for the CXCL12 chemokine, one of which is CXCR4$^{1013}$. We investigated whether CXCR4$^{1013}$ interferes in the HPV18 life cycle in epithelial organotypic cultures. Expression of CXCR4$^{1013}$ promoted stabilization of HPV oncoproteins, thus disturbing cell cycle progression and proliferation at the expense of the ordered expression of the viral genes required for virus production. Conversely, blocking CXCR4$^{1013}$ function restored virus production and limited HPV-induced carcinogenesis. Thus, CXCR4 and its potential activation by genetic alterations in the course of the carcinogenic process can be considered as an important host factor for HPV carcinogenesis.This work was supported by the Institut National de la Santé et de la Recherche Médicale (FM, LC, CD, AJR, FG, PC, FB), ERA-Net for Research Programmes on Rare Diseases (WHIMThernet 2011-E-RARE 013-01) (FM, FB) and Institut National du Cancer (Chemokine-HPV TRANSLA11-077) (FM, CD, FB). We acknowledge funding from the French Laboratory of Excellence project LERMIT (Investissements d’Avenir-ANR-10-LABX-0033-LERMIT) (FM, AJR, PC, FB) and fellowship (FM) from the Fondation ARC pour la recherche sur le cancer