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（由申请方提供）：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的必要步骤。HPV在宫颈癌中的作用已得到很好的阐明;然而，大多数HPV感染不会导致宫颈病变。这导致了一个假设，即辅助因子存在，有助于这一过程。已经阐明的这些辅因子之一是与致癌病毒Epstein-Barr（EBV）的共感染，因为同时脱落HPV和EBV的HIV+妇女具有2-4倍增加的宫颈病理风险。HPV也与其他肛门生殖器癌症有关，特别是肛门疾病。患有宫颈疾病的艾滋病毒阳性和艾滋病毒阴性妇女也有患与HPV有关的肛门发育不良和肛门癌的高风险。艾滋病毒阳性妇女的肛管感染率实际上高于宫颈感染率，但肛门癌的发病率较低。这意味着辅因子在这一过程中的作用甚至更大。以前曾报道过可以在肛门样本中检测到EBV。初步数据显示，来自HIV+个体的存档样本的检出率相似（33%）。此外，目前正在从新奥尔良艾滋病毒阳性和艾滋病毒阴性妇女的纵向队列中收集肛门样本。因此，假设EBV从肛门脱落并作为HPV相关肛门疾病的辅因子。如果EB病毒在肛门癌的发生中与宫颈癌的发生中具有相似的作用，那么就可以得出：（1）在诊断肛门发育不良时，与正常肛门组织相比，更多的肛门样本中存在EBV和高致癌风险HPV。（流行病学关系），（2）在肛门病变发展之前在肛门样品中检测到EBV和HPV（时间关系）和（3）EBV和HPV将位于患病的肛门组织中（空间关系）。这项竞争性修订的目标（NOT-OD-09-058：NIH宣布为竞争性修订申请提供恢复法案资金）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，由于异常肛门Pap涂片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。我们认为，这一为期2年的提案将迅速确立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相互作用的机制。然后，这些数据可以用于确保长期资金，以进一步探索这些相互作用在临床（疾病预防）以及细胞（相互作用机制）水平。 公共卫生相关性：人乳头瘤病毒是大多数肛门癌病例的原因;然而，大多数感染这种病毒的妇女不会进展到癌前病变或癌性病变，这意味着在这个过程中需要辅助因子。越来越多的证据表明，另一种致癌病毒，EB病毒（EBV），是潜在的辅因子，特别是在那些也感染艾滋病毒的妇女中。这项研究将进一步探索EBV在HPV相关肛门癌发展中的作用。