Role of HIV in acceleration of HPV malignancy

项目概要/摘要 越来越多的证据表明，艾滋病毒阳性个体中HPV相关肿瘤的发生率是 尽管进行了有效的抗逆转录病毒治疗，但仍大大高于艾滋病毒阴性个体。这些数据强烈 提示HIV可能在HPV相关的肛门、子宫颈肿瘤的发生中起关键作用， 口咽腔然而，人们对它这样做的机制知之甚少。我们的出版 工作和初步数据表明，艾滋病毒可能与口腔和肛门上皮细胞相互作用， 上皮细胞失去紧密和粘附连接的微环境。这些上皮细胞 与上皮-间充质转化（EMT）一致的变化，EMT是一种多步骤的表观遗传过程， 通过细胞粘附的丧失和上皮细胞的移动性增加。EMT在细胞分化过程中是重要的。 胚胎发生，而且在肿瘤进展中起关键作用。我们的数据显示，口腔和肛门 从HIV感染个体获得的粘膜上皮活检显示出典型的EMT迹象，即，的 粘附连接蛋白E-cadherin表达下调，波形蛋白表达上调。暴露 来自HIV未感染个体的扁桃体上皮细胞与HIV达特和gp 120蛋白的结合导致EMT的诱导。 此外，我们观察到HIV感染与促炎性细胞因子的升高有关， 坏死因子α（TNF-α）和干扰素γ（IFN-γ）在粘膜上皮细胞，这也可能涉及 做急诊急救最后，已知HPV癌蛋白E6/E7可诱导EMT表型。因此，在本发明中， HIV和HPV可通过几种途径与粘膜上皮细胞相互作用， 协同建立EMT，从而增强HPV相关瘤形成。一般来说，EMT 表型是可逆的，EMT细胞可以在EMT和正常状态之间来回转换， 这一过程称为间充质-上皮转化（MET）。诱导MET或抑制EMT可能 代表预防和治疗HPV相关口咽、宫颈和肛门疾病的新方法 可能是一种新的方法，以减少高发病率的HPV相关恶性肿瘤的艾滋病毒- 感染的人。因此，本研究的具体目标是：（1）探讨HIV相关EMT的发生机制 在宫颈和肛门粘膜上皮细胞中，通过抑制波形蛋白诱导MET， E-cadherin表达上调，（2）研究HIV和HPV在发展中的协同作用， EMT表型;（3）研究抑制HIV和HPV诱导的EMT和激活EMT的作用。 MET减少HPV相关的宫颈和肛门细胞转化和侵袭。知识 通过这项工作产生的将是非常有价值的了解艾滋病毒和HPV的机制， 相互作用以增强HPV相关上皮瘤形成的发展。这些知识也可能导致 开发可用于治疗HPV相关癌症和癌前病变的化合物， 通过抑制HIV/HPV诱导的EMT和激活MET来建立HIV感染。

Project summary/Abstract Accumulating evidence indicates that the incidence of HPV-associated neoplasia in HIV-positive individuals is substantially higher than in HIV-negative individuals despite effective antiretroviral therapy. These data strongly suggest that HIV may play a critical role in development of HPV-associated neoplasia of the anus, cervix and oropharyngeal cavity. However the mechanisms by which it does so are poorly understood. Our published work and preliminary data show that HIV may interact with oral and anal epithelia creating a tissue microenvironment where epithelial cells lose tight and adherence junctions. These epithelia have multiple changes consistent with epithelial-mesenchymal transition (EMT), a multistep epigenetic process characterized by loss of cell adhesion and increased mobility of epithelial cells. EMT is important in cell differentiation during embryogenesis but also plays a critical role in neoplastic progression. Our data show that oral and anal mucosal epithelial biopsies obtained from HIV-infected individuals show typical signs of EMT, i.e., the adherens junction protein E-cadherin is down-regulated and vimentin expression is up-regulated. Exposure of tonsil epithelial cells from HIV-uninfected individuals to HIV tat and gp120 proteins leads to induction of EMT. Additionally we observed that HIV infection is associated with elevation of proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) in mucosal epithelia, which may also be involved in induction of EMT. Finally, it is known that HPV oncoproteins E6/E7 can induce the EMT phenotype. Thus, there are several pathways through which HIV and HPV may interact with mucosal epithelia, and may synergize to establish EMT with consequent potentiation of HPV-associated neoplasia. In general the EMT phenotype is reversible and EMT cells may transition back and forth between EMT and the normal state, a process known as mesenchymal-epithelial transition (MET). Induction of MET or inhibition of EMT may represent a novel approach to prevention and treatment of HPV-associated oropharyngeal, cervical and anal neoplasia and may be a novel approach to reducing the high incidence of HPV-associated malignancy in HIV- infected individuals. Accordingly, our specific aims are: (1) To investigate mechanisms of HIV-associated EMT in cervical and anal mucosal epithelial cells and induction of MET in these cells by suppression of vimentin and upregulation of E-cadherin expression, (2) To investigate synergy between HIV and HPV in development of the EMT phenotype, and (3) To study the role of suppression of HIV- and HPV- induced EMT and activation of MET in the reduction of HPV-associated cervical and anal cell transformation and invasion. Knowledge generated through this work will be of great value to understanding the mechanisms by which HIV and HPV interact to potentiate development of HPV-associated epithelial neoplasia. This knowledge may also lead to development of compounds that may be useful for treatment of HPV-associated cancers and pre-cancers in the setting of HIV infection through inhibition of HIV/HPV-induced EMT and activation of MET.