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），高危型HPV（16,18和其他）感染与大多数肛门生殖器恶性肿瘤有关。感染艾滋病毒的妇女感染人乳头瘤病毒、持续感染人乳头瘤病毒、宫颈异常和宫颈癌的风险较高。尽管许多HIV阳性妇女感染了HPV，即使在这些免疫抑制的人群中，相对较少的妇女进展为宫颈异常，这表明HPV感染是必要的，但不是宫颈癌发展的充分条件。因此，其他辅助因素必须增强HPV的致癌潜力。已知的致癌病毒，爱泼斯坦-巴尔病毒（EBV），从子宫颈脱落，使其成为hpv相关宫颈发育不良的主要辅助因素候选。初步数据显示，来自新奥尔良的HIV阳性妇女（n=531）或来自WIHS队列的一项初步研究（n=308），可检测到宫颈HPV和EBV的妇女并发鳞状上皮内病变（SIL）的风险更高（68%），而仅可检测到HPV的妇女只有45%。此外，宫颈异常的HIV阳性女性更有可能发展。EBV的宫颈脱落，这种病毒引起人类恶性肿瘤的潜力，以及我们的初步数据使我们假设EBV在HIV+妇女中hpv诱导的宫颈异常的发生和进展中起着辅助因素的作用。根据这一假设，预测(1)EBV、HPV宫颈共脱落和发育不良的危险因素是相同的（流行病学关系）；(2) EBV和HPV将在发育不良之前脱落，并在进展到更高级别病变的女性中持续存在（时间关系）；(3)定位这两种癌病毒，便于相互作用（空间关系）；(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相互作用也将出现在高风险的hiv阴性妇女中。这四个具体目标将检验这些预测，并为这两种癌病毒之间相互作用的机制提供初步见解：确定EBV和高致癌性HPV在HIV+和高风险HIV阴性妇女中共同脱落的危险因素。2. 确定EBV和HPV在HIV阳性和高危HIV阴性妇女宫颈发育不良中的时间关系。3. 确定EBV和HPV在HIV阳性和HIV阴性高危妇女宫颈发育不良中的空间关系。4. 初步确定EBV和HPV在宫颈发育不良中的功能关系。这些研究将更好地确定EBV与HPV在宫颈发育不良中的相互作用，并将初步了解这种相互作用的机制。这可能会导致改进预防宫颈癌的方法，特别是对艾滋病毒阳性妇女。

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.