Role of HIV in acceleration of HPV malignancy

HIV 在加速 HPV 恶性肿瘤中的作用

基本信息

批准号：
10521250
负责人：
SHAROF M TUGIZOV
金额：
$ 36.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10521250
关键词：
Acceleration Adherence Adherens Junction Anogenital cancer Anus Back Binding Biopsy CCR5 gene CD4 Positive T Lymphocytes CXCR4 gene Cell Adhesion Cell Differentiation process Cell Proliferation Cells Cervical Cervix Uteri Chemosensitization Data Dendritic Cells Development Disease E-Cadherin Embryonic Development Epigenetic Process Epithelial Cells Epithelium Gelatinase A Goals HIV HIV Envelope Protein gp120 HIV Infections HIV Seronegativity HIV Seropositivity HIV therapy HPV oropharyngeal cancer Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papillomavirus 16 Immune response Incidence Individual Inflammatory Integrins Interferon Type II Interferons Invaded Knowledge Lead Macrophage Malignant neoplasm of anus Malignant neoplasm of cervix uteri Mediating Mesenchymal Molecular Mucous Membrane Neoplasms Neoplastic Processes Normal tissue morphology Oncoproteins Oral Oropharyngeal Papillomavirus Transforming Protein E6 Pathway interactions Penetration Phenotype Play Prevention approach Process Proliferating Proteins Public Health Publishing Research Risk Role Squamous intraepithelial lesion TNF gene TNFRSF1A gene Tight Junctions Tissues Tonsil Up-Regulation Vimentin Viral Work antiretroviral therapy attenuation cell motility cell transformation cytokine epithelial to mesenchymal transition keratinocyte migration monocyte novel strategies novel therapeutics oral cavity epithelium premalignant protein E receptor restoration synergism tat Protein tissue culture tumor progression

项目摘要

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.

项目概要/摘要越来越多的证据表明，HIV 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，但仍显着高于艾滋病毒阴性个体。表明 HIV 可能在 HPV 相关的肛门、子宫颈和然而，我们对口咽腔的机制知之甚少。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，形成组织上皮细胞紧密失去和粘附连接的微环境。与上皮间质转化（EMT）一致的变化，这是一个多步骤的表观遗传过程细胞粘附力的丧失和上皮细胞流动性的增加在细胞分化过程中很重要。我们的数据表明，胚胎发生在肿瘤进展中也起着关键作用。从 HIV 感染者身上获得的粘膜上皮活检显示出典型的 EMT 迹象，即粘附连接蛋白 E-钙粘蛋白下调，波形蛋白表达上调。将来自未感染 HIV 的个体的扁桃体上皮细胞转化为 HIV tat 和 gp120 蛋白会导致 EMT 的诱导。此外，我们观察到 HIV 感染与促炎细胞因子肿瘤的升高有关粘膜上皮细胞中的坏死因子α（TNF-α）和干扰素γ（IFN-γ）也可能参与其中最后，已知 HPV 癌蛋白 E6/E7 可以诱导 EMT 表型。 HIV 和 HPV 可能通过多种途径与粘膜上皮相互作用，并且可能协同作用以建立 EMT，从而增强 HPV 相关肿瘤。表型是可逆的，EMT细胞可以在EMT和正常状态之间来回转换，称为间充质-上皮转化 (MET) 的过程可能会诱导 MET 或抑制 EMT。预防和治疗 HPV 相关口咽、宫颈和肛门感染的新方法瘤形成，可能是降低 HIV 患者 HPV 相关恶性肿瘤高发病率的新方法因此，我们的具体目标是： (1) 研究 HIV 相关 EMT 的机制。在宫颈和肛门粘膜上皮细胞中，并通过抑制波形蛋白和在这些细胞中诱导 MET E-钙粘蛋白表达上调，(2) 研究 HIV 和 HPV 在发展中的协同作用 EMT 表型，以及 (3) 研究抑制 HIV 和 HPV 诱导的 EMT 和激活 MET 减少 HPV 相关宫颈和肛门细胞转化和侵袭的知识。通过这项工作产生的结果对于了解 HIV 和 HPV 的机制具有重要价值。相互作用以促进 HPV 相关上皮瘤形成的发展。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 来设置 HIV 感染。