Interaction of EBV and HPV in the Development of Cervical Dysplasia in HIV+ Women

EBV 和 HPV 的相互作用在 HIV 女性宫颈发育不良的发展中

• 批准号: 7616766
• 负责人: MICHAEL E HAGENSEE
• 金额: $ 37.05万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-21 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616766
• 关键词: Anti-Retroviral Agents; Archives; Biopsy; Biopsy Specimen; CD8B1 gene; Cancer Etiology; Cancerous; Cells; Cervical; Cervical dysplasia; Cervix Uteri; Data; Development; Disease; Dysplasia; Epidemiology; Epithelial Cells; Growth; HIV; HPV-High Risk; High Risk Woman; Human; Human Herpesvirus 4; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immune; Immunity; Infection; Lead; Lesion; Liquid substance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Methods; Nature; Oncogenic; Oncogenic Viruses; Oncornaviruses; Pilot Projects; Population; Process; Relative (related person); Risk; Risk Factors; Role; Sampling; Sexually Transmitted Diseases; Space Perception; Squamous intraepithelial lesion; Staining method; Stains; T-Lymphocyte; Testing; Tissue Stains; Tissues; Viral; Virus; Woman; cofactor; cohort; cytokine; high risk; improved; insight; prevent; spatial relationship

DESCRIPTION (provided by applicant): Human papillomavirus (HPV) infection of anogenital tissues has been implicated as a requisite step in the progression to neoplastic transformation. The role of HPV in cervical cancer has been well elucidated; however, most infections with HPV do not lead to cervical pathology. This leads to the hypothesis that co- factor(s) are present that assist in this process. One of these co-factors that have been elucidated is co- infection with the oncogenic virus, Epstein-Barr (EBV) as HIV+ women co-shedding both HPV and EBV have a 2-4 fold increased risk of cervical pathology. HPV has also been implicated in other anogenital cancers especially anal disease. Both HIV+ and HIV-negative women with cervical disease are also at high risk for developing anal dysplasia and anal cancers related to HPV. The infection rates of the anal canal in HIV+ women are actually higher than cervical but the rates of anal cancer are lower. This implies an even stronger role for co-factor(s) in this process. It has been previously reported that EBV can be detected in anal samples. Preliminary data demonstrates similar detection rates (33%) from archived samples from HIV+ individuals. In addition, anal samples are now being collected from the ongoing longitudinal cohorts of HIV+ and HIV-negative women from New Orleans. Thus, it is hypothesized that EBV is shed from the anus and serves as a co- factor for HPV-related anal disease. If EBV has a similar role in the development of anal cancer as it does in cervical cancer than it follows that: (1) EBV and high oncogenic risk HPV will be present in more anal samples at the time of diagnosis of anal dysplasia than in normal anal tissues (epidemiological relationship), (2) EBV and HPV will be detected in anal samples prior to the development of anal lesions (temporal relationship) and (3) EBV and HPV will be located in diseased anal tissues (spatial relationship). The goal of this competitive revision (NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications) is to extend the ongoing study into an examination of the role of EBV in HPV-related anal dysplasia and cancer utilizing the existing clinical cohorts. In addition, anal tissue that will be obtained for pathological diagnosis due to an abnormal anal Pap smear will be examined for the location of EBV and HPV in relation to the anal disease as well as differential gene expression. It is felt that this 2 year proposal will quickly establish a role for EBV in anal dysplasia as well as begin to elucidate the mechanism of interaction between these two oncogenic viruses. These data can then be utilize to secure longer term funding to further explore these interactions at both the clinical (prevention of disease) as well as cellular (mechanism of interaction) level. PUBLIC HEALTH RELEVANCE: Human papillomavirus is the cause of most cases of anal cancer; however, most women infected with this virus do not progress to pre-cancer or cancerous lesions implying the need for co-factors in this process. Accumulated evidence points to another cancer-causing virus, Epstein-Barr virus, (EBV), as the potential co- factor, particularly in those women also infected by the HIV virus. The proposed research will further explore the role of EBV in the development HPV-related anal cancer.

描述（由申请人提供）：肛门生殖器组织的人乳头瘤病毒（HPV）感染被认为是肿瘤转化进展中的必要步骤。 HPV 在宫颈癌中的作用已得到充分阐明；然而，大多数 HPV 感染不会导致宫颈病变。这导致了这样的假设：存在辅助该过程的辅因子。已阐明的这些辅助因素之一是与致癌病毒 Epstein-Barr (EBV) 的共同感染，因为同时感染 HPV 和 EBV 的 HIV+ 女性患宫颈病变的风险增加 2-4 倍。 HPV 还与其他肛门生殖器癌症尤其是肛门疾病有关。患有宫颈疾病的 HIV 阳性和 HIV 阴性女性也面临着与 HPV 相关的肛门发育不良和肛门癌的高风险。 HIV阳性女性的肛管感染率实际上高于宫颈癌，但肛门癌的发病率较低。这意味着辅助因子在此过程中发挥着更强大的作用。此前有报道称，肛门样本中可检测到EBV。初步数据显示，HIV+ 个体的存档样本的检出率相似 (33%)。此外，现在正在从新奥尔良的艾滋病毒+和艾滋病毒阴性女性的持续纵向队列中收集肛门样本。因此，推测 EBV 从肛门排出并作为 HPV 相关肛门疾病的辅助因子。如果 EBV 在肛门癌的发展中具有与宫颈癌相似的作用，则如下：（1）在诊断肛门发育不良时，EBV 和高致癌风险 HPV 将存在于比正常肛门组织更多的肛门样本中（流行病学关系），（2）EBV 和 HPV 将在肛门病变发展之前在肛门样本中检测到（时间关系），以及（3）EBV 和 HPV HPV 将位于患病的肛门组织中（空间关系）。此次竞争性修订（NOT-OD-09-058：NIH 宣布为竞争性修订申请提供恢复法案资金）的目标是将正在进行的研究扩展到利用现有临床队列检查 EBV 在 HPV 相关肛门发育不良和癌症中的作用。此外，由于肛门巴氏涂片异常而获得的用于病理诊断的肛门组织将检查与肛门疾病相关的EBV和HPV的位置以及差异基因表达。人们认为，这项为期两年的提案将很快确定 EBV 在肛门发育不良中的作用，并开始阐明这两种致癌病毒之间的相互作用机制。然后可以利用这些数据来获得长期资金，以进一步探索临床（疾病预防）和细胞（相互作用机制）水平上的这些相互作用。 公共卫生相关性：人乳头瘤病毒是大多数肛门癌病例的病因；然而，大多数感染这种病毒的女性不会进展为癌前病变或癌性病变，这意味着这一过程中需要辅助因子。积累的证据表明另一种致癌病毒，EB 病毒 (EBV)，是潜在的辅助因素，特别是对于那些也感染 HIV 病毒的女性。拟议的研究将进一步探讨 EBV 在 HPV 相关肛门癌发展中的作用。