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）感染是最常见的病毒性性传播感染（STI），大多数肛门生殖器恶性肿瘤涉及高危型HPV（16、18和其他）感染。感染HIV的妇女感染HPV、持续性HPV感染、宫颈异常和宫颈癌的风险较高。虽然许多HIV阳性的妇女感染了HPV，但即使在这种免疫抑制的人群中，相对较少的妇女发展为宫颈异常，这表明HPV感染是必要的，但不足以发展为宫颈癌。因此，其他辅助因子必须增加HPV的致癌潜力。已知的致癌病毒Epstein-Barr病毒（EBV）从宫颈脱落，使其成为HPV相关宫颈发育不良的主要辅助因子候选者。初步数据显示，来自新奥尔良（n=531）或来自WIHS队列（n=308）的可检测到宫颈HPV和EBV的HIV+妇女并发鳞状上皮内病变（SIL）的风险较高（68%），而仅检测到HPV的妇女仅为45%。此外，宫颈异常的共同脱落艾滋病毒+妇女更有可能进展。EB病毒的宫颈脱落、该病毒导致人类恶性肿瘤的潜力以及我们的初步数据使我们假设EB病毒在HIV+女性中HPV诱导的宫颈异常的发生和进展中起辅助因素的作用。根据这一假设，可以预测：（1）宫颈共同脱落的EBV和HPV和异型增生的危险因素将是相同的（流行病学关系）;（2）EBV和HPV将在发育不良发生之前脱落，并在进展到更高级别病变的女性中持续存在（时间关系）;（3）这两种肿瘤病毒将被定位，以促进相互作用（4）EBV和HPV会感染宫颈上皮细胞并直接或间接相互作用（功能关系）。据预测，这种EBV-HPV相互作用也将在高危HIV阴性妇女中观察到。四个具体目标将测试这些预测，并提供初步的见解，这两种肿瘤病毒之间的相互作用机制：1。确定HIV+和高危HIV阴性女性中EBV和高致癌风险HPV共同脱落的风险因素。2.确定EBV和HPV在HIV+和高危HIV阴性妇女宫颈不典型增生发展中的时间关系。3.确定EBV和HPV在HIV+和高危HIV阴性妇女宫颈不典型增生发展中的空间关系。4. EBV和HPV在宫颈不典型增生发生中功能关系的初步确定这些研究将更好地定义EBV与HPV在宫颈发育不良发展中的相互作用，并将提供对这种相互作用机制的初步了解。这可能会导致预防宫颈癌的方法得到改进，特别是对于艾滋病毒阳性的妇女。 公共卫生相关性：人乳头瘤病毒是大多数宫颈癌病例的原因;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，这意味着在这一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。本研究拟进一步探讨EBV在HPV相关宫颈癌发生发展中的作用。

DESCRIPTION (provided by applicant): Human papillomavirus (HPV) infection is the most common viral sexually transmitted infection (STI), and infection with high-risk types of HPV (16, 18, and others) has been implicated in the majority of anogenital malignancies. HIV-infected women are at higher risk for HPV infection, persistent HPV infection, cervical abnormalities, and cervical cancer. Although many HIV+ women are infected with HPV, even in this immune suppressed population, relatively few women progress to cervical abnormalities, indicating that HPV infection is necessary but not sufficient for development of cervical cancer. Thus, other co-factors must augment the oncogenic potential of HPV. The known oncogenic virus, Epstein-Barr virus (EBV), is shed from the cervix, making this a prime co-factor candidate for HPV-related cervical dysplasia. Preliminary data show that HIV+ women from New Orleans (n=531) or from a pilot study of the WIHS cohort (n=308) with detectable cervical HPV and EBV are at higher risk (68%) for concurrent squamous intraepithelial lesions (SIL) as compared to only 45% of women with only detectable HPV. In addition, cervical abnormalities in co-shedding HIV+ women are more likely to progress. The cervical shedding of EBV, the potential of this virus to cause human malignancy, and our preliminary data have led us to hypothesize that EBV acts as a co-factor in the development and progression of HPV-induced cervical abnormalities in HIV+ women. From this hypothesis, it is predicted that (1) the risk factors for the cervical co-shedding of EBV and HPV and dysplasia will be the same (epidemiological relationship); (2) EBV and HPV will be shed prior to the development of dysplasia and be persistent in women who progress to higher grade lesions (temporal relationship); (3) these two oncoviruses will be located to facilitate interactions (spatial relationship); and (4) EBV and HPV will infect the cervical epithelial cells and interact directly or indirectly (functional relationship). It is also predicted that this EBV-HPV interaction will also be seen in high-risk HIV-negative women. The four specific aims will test these predictions and provide initial insights into the mechanism of interaction between these two oncoviruses: 1. Determine the risk factors for co-shedding of EBV and high oncogenic risk HPV in HIV+ and high- risk HIV-negative women. 2. Determine the temporal relationship between EBV and HPV in the development of cervical dysplasia in HIV+ and high-risk HIV-negative women. 3. Determine the spatial relationship between EBV and HPV in the development of cervical dysplasia in HIV+ and high-risk HIV-negative women. 4. Initial determination of the functional relationship between EBV and HPV in the development of cervical dysplasia. These studies will better define the interaction of EBV with HPV in the development of cervical dysplasia and will provide the initial understanding of the mechanism of this interaction. This could lead to improved methods to prevent cervical cancer, especially for HIV+ women. PUBLIC HEALTH RELEVANCE: Human papillomavirus is the cause of most cases of cervical 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. This proposal is to further explore the role of EBV in the development HPV-related cervical cancer.