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

描述（由申请人提供）：人乳头瘤病毒（HPV）感染肛门生殖器组织已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。这就产生了一种假设，即辅助因素存在于这一过程中。其中一个已被阐明的辅助因素是与致癌病毒EBV （Epstein-Barr， EBV）的共同感染，因为同时脱落HPV和EBV的HIV阳性妇女发生宫颈病理的风险增加2-4倍。HPV也与其他肛门生殖器癌症，特别是肛门疾病有关。患有宫颈疾病的艾滋病毒阳性和艾滋病毒阴性妇女患与HPV相关的肛门发育不良和肛门癌的风险也很高。艾滋病毒阳性妇女的肛管感染率实际上高于宫颈，但肛门癌的发病率较低。这意味着辅助因素在这个过程中的作用更大。以前有报道说，在肛门样本中可以检测到EBV。初步数据显示，来自艾滋病毒阳性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相关肛门疾病的辅助因素。如果EBV在肛门癌的发展有一个类似的角色比此前在宫颈癌:(1)EBV和高致癌HPV风险将会出现在更多的肛交样品的时候比在正常肛门发育异常的诊断肛门组织(流行病学关系),(2)巴尔病毒和人乳头状瘤病毒将在肛门样品检测前肛门病变的发展(时间关系)和(3)巴尔病毒和人乳头状瘤病毒将位于病变的肛门组织(空间关系)。这项竞争性修订的目标（NOT-OD-09-058: NIH宣布恢复法案基金可用于竞争性修订申请）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，由于肛门涂片异常而获得的肛门组织将用于病理诊断，将检查EBV和HPV与肛门疾病的关系以及差异基因表达的位置。我们认为，这项为期2年的研究将很快确立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。然后可以利用这些数据获得长期资助，在临床（疾病预防）和细胞（相互作用机制）水平上进一步探索这些相互作用。

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.