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: 7495472
• 负责人: MICHAEL E HAGENSEE
• 金额: $ 42万
• 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/7495472
• 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; Epithelial Cells; Growth; HIV; HPV-High Risk; High Risk Woman; Human; Human Development; 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; Public Health; Relative (related person); Risk; Risk Factors; Role; Sampling; Sexually Transmitted Diseases; Space Perception; Squamous intraepithelial lesion; T-Lymphocyte; Testing; Tissue Stains; Tissues; Viral; Virus; Woman; cofactor; cohort; cytokine; improved; insight; prevent; spatial relationship

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.

描述（由申请人提供）：人类乳头瘤病毒（HPV）感染是最常见的病毒性传播感染（STI），并且具有高风险的HPV（16、18等）感染与大多数肛门生态恶性肿瘤有关。 HIV感染的妇女患HPV感染，持续性HPV感染，宫颈异常和宫颈癌的风险更高。尽管许多HIV+女性感染了HPV，但即使在这种免疫抑制人群中，相对较少的妇女会发展为宫颈异常，这表明HPV感染是必要的，但不足以发展为宫颈癌。因此，其他共同因素必须增强HPV的致癌潜力。已知的致癌病毒Epstein-Barr病毒（EBV）是从子宫颈脱离的，使其成为HPV相关宫颈发育不良的主要辅助因子候选者。初步数据表明，来自新奥尔良的HIV+女性（n = 531）或来自WIHS队列的试点研究（n = 308），与仅45％的女性相比，与仅45％的女性相比，与仅45％的女性相比，同意的鳞状上皮内病变（SIL）的可检测到的宫颈HPV和EBV的风险更高（68％）。此外，共同释放的艾滋病毒+女性的宫颈异常更有可能进展。 EBV的宫颈脱落，该病毒引起人类恶性肿瘤的潜力，以及我们的初步数据导致我们假设EBV在HPV诱导的HIV+女性中HPV诱导的宫颈异常的发育和进展中起着共同因素的作用。从这一假设中可以预测，（1）EBV和HPV和发育不良的宫颈共脱落的危险因素将是相同的（流行病学关系）； （2）EBV和HPV将在发育不良发展之前脱离，并在发展高年级病变的妇女中持续存在（时间关系）； （3）这两个野毒病毒将被定位以促进相互作用（空间关系）； （4）EBV和HPV将感染宫颈上皮细胞并直接或间接相互作用（功能关系）。还可以预测，这种EBV-HPV相互作用也将在高风险的HIV阴性女性中看到。四个具体目标将测试这些预测，并提供有关这两种野兽病毒之间相互作用机制的初步见解：1。确定HIV+和高风险HIV HIV（HIV）妇女在HIV+和高风险HPV中共同进行的风险因素。 2。确定HIV+和高风险HIV阴性妇女在宫颈发育不良发展中EBV和HPV之间的时间关系。 3。确定HIV+和高危HIV阴性女性在宫颈发育不良发展中EBV与HPV之间的空间关系。 4。宫颈发育不良发展中EBV和HPV之间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理解。这可能会导致改进的预防宫颈癌的方法，尤其是对于HIV+女性。 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；但是，大多数感染该病毒的妇女不会发展为癌症或癌性，这意味着在此过程中需要副因素。积累的证据表明，另一种引起癌症的病毒Epstein-Barr病毒（EBV）是潜在的共同因素，特别是在那些也感染了HIV病毒的妇女中。该建议是进一步探讨EBV在与HPV相关的宫颈癌发育中的作用。