Natural History & Pathogenesis of HPV in HIV infected women with cervical cancer

中低收入国家的子宫颈癌负担约占全球子宫颈癌总发病率的80%。在博茨瓦纳，艾滋病毒阳性妇女宫颈癌发病率增加之间的联系尚未得到仔细探讨。此外，最近的其他研究表明，传染病与癌症之间的联系日益密切，包括与默克尔细胞多瘤病毒有关的默克尔细胞癌的存在。这强调了这些药物的重要性及其对致癌过程的贡献。超过20%的人类癌症与传染因子有关，这一估计可能低于实际数字。技术和方法的进步，包括从组织和其他材料中恢复核酸，大大提高了我们在相关癌症中检测和确认这些因子的能力。项目#1中拟议研究的总体目标是确定感染因子对博茨瓦纳艾滋病毒阳性妇女宫颈癌发展的贡献。博茨瓦纳艾滋病毒阳性妇女宫颈癌发病率的急剧增加，考虑到其他因素以及炎症反应的潜在作用，它们共同导致更迅速和更增殖的反应。我们的项目将利用我们在波士顿独特的3组妇女，这使我们能够监测HPV和HIV阴性妇女和HIV和HPV阳性宫颈癌妇女的宫颈菌群变化。我们最初的问题将是确定可能与该人群宫颈癌发展有关的其他因素（微生物特征）。我们的工作假设是，多种药物可能导致博茨瓦纳hiv阳性妇女宫颈癌的发展，这可能导致炎症反应（炎症特征），从而协同导致宫颈癌。我们将利用我们新开发的组合策略，将微阵列技术与高通量测序相结合。在确定这些药物之后，将验证这些药物在组织中的存在，对感染细胞进行转录分析，以及对相关药物的先天和适应性炎症反应进行分析，并使用原代宫颈上皮细胞的体外模型系统研究这些细胞的增殖作用。

The cervical cancer burden in low and middle income countries make up about 80% of the total cervical cancer incidence worldwide. In Botswana the link between increased incidences of cervical cancer in HIV positive women has not been carefully explored. Furthermore there is an increased link between infectious disease and cancer as seen by additional recent studies including the presence of Merkel Cell Carcinomas linked to the Merkel Cell Polyoma virus. This underscores the importance of these agents and their contributions to the oncogenic process. Greater than 20% of human cancers are associated with infectious agents and that estimate is likely to be lower than the actual number. The advances in technology and approaches which include recovery of nucleic acids from tissues and other materials has greatly improved our ability to detect and confirm the identifications of these agents in associated cancers. The overall goal of the proposed studies in project #1 is to determine the contributions of infectious agents to development of cervical carcinomas in HIV positive women in Botswana. This dramatic increase in cervical cancer incidence in HIV-positive women in Botswana allows for the potential contributions of additional agents as well as the inflammatory response which together leads to a more rapid and proliferative response. Our project will take advantage of our unique 3 cohorts of women in Bostwana that allows us to monitor changes in the cervical flora from HPV and HIV-negative women to women with cervical cancer who are HIV and HPV positive. Our initial question will be to identify additional agents (microbial signature) which may be linked to development of cervical carcinomas in this population. Our working hypothesis is that multiple agents can contribute to the development of cervical carcinomas in HIV-positive women in Botswana and this can result in an inflammatory response (inflammatory signature) which synergistically leads to cervical carcinomas. We will utilize our newly developed combinatorial strategy which bridges microarray technology with high throughput sequencing. The identification of these agents will be followed by validation of the presence of these agents in tissues, transcription analysis of infected cells as well as analysis of the innate and adaptive inflammatory responses with the associated agents, and investigating the proliferative effects on these cells using an in vitro model system of primary cervical epithelial cells.