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 CXCR41013. We investigated whether CXCR41013 interferes in the HPV18 life cycle in epithelial organotypic cultures. Expression of CXCR41013 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 CXCR41013 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.

产毒性人乳头瘤病毒（HPV）的增殖周期与角质形成细胞的分化及增殖过程紧密关联。上述过程的失调，以及病毒癌蛋白与宿主细胞因子共同作用介导的细胞增殖刺激，是HPV介导致癌作用的分子基础。疣、低丙种球蛋白血症、感染与粒细胞缺乏症（WHIM）免疫缺陷综合征以严重HPV感染为典型特征，该综合征由CXCL12趋化因子的受体CXCR4发生功能获得性突变所引发，其中一类突变体即为CXCR41013。本研究探究了CXCR41013是否会在上皮类器官培养中干扰HPV18的增殖周期。实验结果表明，CXCR41013的表达可促进HPV癌蛋白的稳定积累，进而以牺牲病毒增殖所需的病毒基因有序表达为代价，扰乱细胞周期进程与细胞增殖活性。反之，阻断CXCR41013的功能可恢复病毒生成能力，并抑制HPV诱导的致癌进程。综上，CXCR4及其在致癌过程中因遗传改变产生的潜在激活效应，可被视为HPV致癌过程中的关键宿主因子。