HIV induced anti-cancer HERV immunity in prostate, breast and colon cancers

HIV 诱导前列腺癌、乳腺癌和结肠癌中的抗癌 HERV 免疫

• 批准号: 9129387
• 负责人: DOUGLAS F NIXON
• 金额: $ 53.17万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-19 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129387
• 关键词: Allogenic; Antibody Response; Antigens; Apoptosis; Applications Grants; Blocking Antibodies; Breast Cancer Cell; Cancer Etiology; Cells; Chromosomes; Colon Carcinoma; Data; Data Set; Detection; Development; Disease; Endogenous Retroviruses; Family; Frequencies; Funding; Germ cell tumor; HIV; HIV Infections; HK2 gene; Human; Human Genome; Immune response; Immunity; Immunologic Monitoring; Immunologic Techniques; In Vitro; Incidence; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular; Pathogenesis; Pathway interactions; Patients; Pattern; Proteins; Publishing; RNA; Renal Cell Carcinoma; Renal carcinoma; Research; Retrovirus Proteins; Role; Source; Stem Cell Development; Stem cell transplant; System; T-Lymphocyte; Testing; Time; Translating; United States National Institutes of Health; Viremia; cancer type; embryonic stem cell; insight; malignant breast neoplasm; melanoma; novel; particle; programs; public health relevance; response; stem; tumor

 DESCRIPTION (provided by applicant): This new R01 application is in response to the RFA-CA-15-012 "Provocative Questions in Cancer with an Underlying HIV Infection (R01)", and responds to PQ6: "Why are only certain cancer types increased whereas others are unchanged or even decreased in people with HIV infection"? Over the past decade our group has published on the effect of HIV infection on the expression of human endogenous retroviruses (HERVs). We have focused on the most recent HERV in the human genome, HML-2, abbreviated to HK2. Our data shows that in an HIV infected cell, HK2 is transcribed and products are translated, and that this is dependent on HIV Vif. CTL generated against HK2 can eliminate HIV infected cells in vitro. Furthermore, we have found that elite controllers have higher frequencies of HK2 specific CTL and antibody responses. This suggests that in patients with HIV infection, anti-HK2 immune responses could be part of the immunosurveillance system to keep viremia in check. In human cancers, HERVs have been suspected to be involved in pathogenesis of some cancers, with the detection of HERV expression in germ cell tumors, prostate and breast cancers, melanoma, renal cell carcinoma. However, HK2 RNA, protein, and particle expression during cancers does not ascribe a definitive role for HK2 activity in contributing to cancer etiology in humans. A number of cancers are not increased in incidence in HIV infection or are even decreased, such as breast, prostate or colon cancer. We have recently developed a novel computational pathway program, "telescope", which can use RNASeq data sets to pinpoint loci on a chromosome in which HERVs are transcribed. In preliminary studies, we have used this pathway to locate HERV expression in the context of an HIV infected cell, and find distinct chromosomal patterns of HERV expression. We hypothesize that HIV reactivation of HERV's stimulates anti-HERV immunity which specifically recognizes HERVs also expressed in prostate, colon and breast cancers, and that these HIV induced HERV specific immune responses which target HERVs which are expressed in breast, colon or prostate cancer. We are proposing three aims: Aim 1: To determine which HERVs are expressed in prostate, breast and colon cancers, in patients with or without HIV infection, using a computational pathway program "telescope" to interrogate RNASeq data from publically available sources. Aim 2: To determine which HERVs are expressed in prostate, breast and colon cancers, in patients with or without HIV infection from material existing within the NIH funded ACSR. Aim 3: To ascertain anti-HERV immune responses in patients with prostate, breast or colon cancers, in patients with or without HIV infection. In this proposal, we aim to develop and test hypotheses, stemming from our preliminary data, that will verify and expand the knowledge of HERV expression in prostate, colon and breast cancers in the presence or absence of HIV infection, and associate specific HERV expression and specific anti-HERV immunity with cancer immunosurveillance.

 描述（由申请人提供）：这项新的 R01 申请是对 RFA-CA-15-012“潜在 HIV 感染癌症的挑衅性问题（R01）”的回应，并回应 PQ6：“为什么在 HIV 感染者中只有某些癌症类型增加，而其他癌症类型没有变化甚至减少”？在过去的十年中，我们的小组发表了有关 HIV 感染对人类内源性逆转录病毒 (HERV) 表达的影响的文章。我们重点关注人类基因组中最新的 HERV，HML-2，缩写为 HK2。我们的数据显示，在 HIV 感染的细胞中，HK2 被转录并且产物被翻译，并且这依赖于 HIV Vif。针对 HK2 产生的 CTL 可以在体外消除 HIV 感染的细胞。此外，我们发现精英控制者具有更高频率的 HK2 特异性 CTL 和抗体反应。这表明，在 HIV 感染患者中，抗 HK2 免疫反应可能是免疫监视系统的一部分，以控制病毒血症。在人类癌症中，HERV 被怀疑参与某些癌症的发病机制，在生殖细胞肿瘤、前列腺癌和乳腺癌、黑色素瘤、肾细胞癌中检测到 HERV 表达。然而，癌症期间 HK2 RNA、蛋白质和颗粒的表达并不能确定 HK2 活性在人类癌症病因学中的决定性作用。许多癌症的发病率在艾滋病毒感染后并未增加，甚至有所减少，例如乳腺癌、前列腺癌或结肠癌。我们最近开发了一种新型计算途径程序“telescope”，它可以使用 RNASeq 数据集来精确定位 HERV 转录所在染色体上的位点。在初步研究中，我们使用该途径来定位 HIV 感染细胞中的 HERV 表达，并发现 HERV 表达的独特染色体模式。我们假设HIV对HERV的重新激活会刺激抗HERV免疫，该免疫特异性识别也在前列腺癌、结肠癌和乳腺癌中表达的HERV，并且这些HIV诱导针对在乳腺癌、结肠癌或前列腺癌中表达的HERV的HERV特异性免疫反应。我们提出三个目标： 目标 1：使用计算途径程序“望远镜”从公开来源询问 RNASeq 数据，确定哪些 HERV 在前列腺癌、乳腺癌和结肠癌中表达，无论是在感染还是未感染 HIV 的患者中。目标 2：根据 NIH 资助的 ACSR 中现有的材料，确定哪些 HERV 在前列腺癌、乳腺癌和结肠癌、感染或未感染 HIV 的患者中表达。目标 3：确定前列腺癌、乳腺癌或结肠癌患者、感染或未感染 HIV 的患者的抗 HERV 免疫反应。在本提案中，我们的目标是根据我们的初步数据提出并测试假设，这些假设将验证和扩展对存在或不存在 HIV 感染的前列腺癌、结肠癌和乳腺癌中 HERV 表达的了解，并将特异性 HERV 表达和特异性抗 HERV 免疫与癌症免疫监视联系起来。