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（应用程序提供）：这种新的R01应用是对RFA-CA-15-012“具有潜在的HIV感染（R01）的癌症中的挑衅性问题（R01）”，并且对PQ6做出了反应：“为什么某些癌症类型只有某些癌症类型增加，而其他癌症类型不变甚至降低了HIV感染的人”？在过去的十年中，我们的小组发表了有关HIV感染对人内源性逆转录病毒（HERV）表达的影响。我们专注于人类基因组HML-2的最新HERV，缩写为HK2。我们的数据表明，在HIV感染的细胞中，HK2被翻译并翻译产品，这取决于HIV VIF。针对HK2产生的CTL可以在体外消除HIV感染的细胞。此外，我们发现精英控制器具有较高的HK2特异性CTL和抗体反应的频率。这表明，在HIV感染患者中，抗HK2免疫复杂可能是免疫监视系统的一部分，以控制病毒血症。在人类的癌症中，怀疑HERV参与了某些癌症的发病机理，并且在生殖细胞肿瘤，前列腺和乳腺癌，黑色素瘤，肾细胞癌中发现了HERV表达。但是，癌症期间的HK2 RNA，蛋白质和颗粒表达并未分配HK2活性在有助于人类癌症病因中的确定作用。艾滋病毒感染的发病率并没有改善，例如乳腺癌，前列腺或结肠癌，许多癌症的发病率没有增加。我们最近开发了一个新颖的计算途径程序“望远镜”，该程序可以使用RNASEQ数据集来查明基因座，以转录HERV的染色体。在初步研究中，我们使用了这种途径来定位HIV感染细胞的情况，并找到HERV表达的不同染色体模式。我们假设HERV的HIV重新激活刺激了抗HERV免疫性，该抗HERV免疫性明确地识别了在前列腺，结肠和乳腺癌中也表达的HERV，并且这些HIV诱导了HERV特异性免疫抑制，该免疫抑制靶向乳腺癌，结肠或前列腺癌表达的HERV。我们提出三个目标：目标1：确定在有或没有HIV感染的患者中，使用计算途径程序“望远镜”来询问公共可用来源的RNASEQ数据，以确定哪些HERV在前列腺，乳腺癌和结肠癌中表达。 AIM 2：确定在NIH资助的ACSR中存在的材料中有或没有HIV感染的患者中，在前列腺，乳腺癌和结肠癌中表达了哪些HERV。目标3：确定患有或没有HIV感染的患者的前列腺，乳腺癌或结肠癌患者的抗HERV免疫复杂。在该提案中，我们旨在根据我们的初步数据来开发和检验假设，这些假设将在存在或不存在HIV感染的情况下验证和扩展前列腺，结肠和乳腺癌中HERV表达的知识，并关联特定的HERV表达和特定的抗HERV免疫保健失败。