Human papillomavirus in HIV associated lung cancers

摘要 近年来，由于HAART治疗，艾滋病定义癌症的发病率大幅下降。 相比之下，非艾滋病定义癌症(NADC)，特别是肺癌(LC)的发病率上升了 超过3折。在美国，LC已成为最常见的NADC，发病率为每年204例 10万人年。LC也是NADC最常见的死亡原因，占癌症的21%。 艾滋病毒(+)人群中的相关死亡。虽然吸烟是HIV相关LCS的关键风险因素，但HIV(+) 在控制了吸烟状态后，个人患LC的风险仍然增加了3倍，这表明其他因素 对这种增加的发病率负有责任。与其他常见的艾滋病毒相关癌症不同，如宫颈癌 癌症、非霍奇金淋巴瘤和卡波西肉瘤，HIV相关LC没有已知的病毒 病因学。为了发现任何与HIV相关的LCS的潜在肿瘤病原体，我们利用了我们的下一个- 基于生成测序的解析流水线，用于询问1,000多个LC RNA-SEQ数据集。我们 发现人类乳头瘤病毒(HPV)与HIV(+)人群中的LCS有因果关系。这个 这项建议的首要目标是确定HPV在HIV相关LCS中的参与情况，使用我们的Well- 已建立的基于测序的信息学方法以及新创建的HPV(+)HIV相关LC 模型系统。我们将首先检验HPV和LCS之间存在因果关系的假设 在艾滋病毒(+)人群中，但在普通人群中不是。此外，我们还将测试HPV是否 增强雌激素介导的生长信号和表达病毒促进肺肿瘤的发生 HIV阳性个体中的E5/E6/E7/HPV-CIRC-880-408癌基因我们将阐明人乳头瘤病毒的关键作用 癌基因产物包括一种新的病毒环状RNA和雌激素介导的生长信号和免疫- 人类免疫缺陷病毒相关肺癌发生中的逃避。我们将同时考察存在的一个重要概念 能够用抗雌激素和/或抗HPV方案精确治疗HPV(+)HIV相关性LC 个性化医疗。此外，通过确定HPV的病因，我们的工作可能有助于通过促进 为男女接种HPV疫苗。总之，这项研究的完成将在概念上增加我们的 了解HIV相关的LC，并提供潜在的独特治疗机会，最终 使部分HIV(+)LC患者受益。

SUMMARY In recent years, the incidence of AIDS-defining cancers has dramatically decreased due to the HAART therapy. In contrast, the incidence of the non-AIDS-defining cancers (NADC), especially lung cancer (LC) has risen by more than 3 fold. In the U.S., LC has become the most common NADC with an incidence rate of 204 cases per 100,000 person-years. LC is also the most common NADC cause of death and accounts for 21% of cancer- related death in the HIV(+) population. Although smoking is a key risk factor for HIV associated LCs, HIV(+) individuals still have a 3-fold increased LC risk after controlling for smoking status, indicating that other factors are responsible for this increased incidence. Unlike other common HIV associated cancers such as cervical cancer, non-Hodgkin's lymphoma, and Kaposi's sarcoma, HIV associated LCs do not have a known viral etiology. To discover any potential oncopathogen for HIV associated LCs, we have utilized our Next- Generation-Sequencing-based PARSES pipeline to interrogate more than 1,000 LC RNA-seq data sets. We discovered that human papillomavirus (HPV) is causally associated with LCs in the HIV(+) population. The overarching goal of this proposal is to determine the involvement of HPV in HIV associated LCs using our well- established sequencing based informatics approaches as well as newly created HPV(+) HIV associated LC model systems. We will first examine the hypothesis that there is a causal association between HPV and LCs in the HIV(+) population but not in the general population. In addition, we will test the hypothesis that HPV promotes lung oncogenesis by enhancing the estrogen-mediated growth signaling and expressing viral E5/E6/E7/hpv-circ-880-408 oncogenes in the HIV(+) individuals. We will elucidate the critical roles of HPV oncogene products including a novel viral circular RNA and estrogen-mediated growth signaling and immune- evasion in HIV associated lung carcinogenesis. We will simultaneously examine an important concept of being able to precisely treat HPV(+) HIV associated LCs with anti-estrogen and/or anti-HPV regimens in the era of personalized medicine. Further, by determining the HPV etiology, our work may help prevent LCs by promoting HPV vaccination for both sexes. Together, completion of the research will add conceptually to our understanding of HIV associated LCs and provide potentially unique therapeutic opportunities and ultimately benefit a subset of HIV(+) LC patients.