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: 9335324
• 负责人: DOUGLAS F NIXON
• 金额: $ 50.87万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335324
• 关键词: Allogenic; Antibody Response; Apoptosis; Applications Grants; Blocking Antibodies; Breast Cancer Treatment; Cancer Etiology; Cells; Chromosomes; Colon Carcinoma; Data; Data Set; Detection; Development; Disease; Endogenous Retroviruses; Family; Frequencies; Funding; Genetic Transcription; Germ cell tumor; HIV; HIV Infections; HK2 gene; Hepatitis B e Antigens; 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 transplant; System; T-Lymphocyte; Testing; Time; Translating; United States National Institutes of Health; Viremia; cancer cell; cancer type; embryonic stem cell; insight; malignant breast neoplasm; melanoma; novel; particle; programs; public health relevance; response; stem; transcriptome sequencing; 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）：该新R 01申请是对RFA-CA-15-012“潜在HIV感染的癌症中的挑衅性问题（R 01）”的回应，并对PQ 6：“为什么HIV感染者中只有某些癌症类型增加，而其他癌症类型不变甚至减少”的回应？在过去的十年中，我们的小组发表了关于HIV感染对人类内源性逆转录病毒（HERVs）表达的影响的文章。我们关注的是人类基因组中最新的HERV，HML-2，缩写为HK 2。我们的数据表明，在HIV感染的细胞中，HK 2被转录并翻译产物，这依赖于HIV Vif。针对HK 2产生的CTL可以在体外清除HIV感染细胞。此外，我们发现精英控制者具有更高频率的HK 2特异性CTL和抗体应答。这表明，在艾滋病毒感染患者中，抗HK 2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，已经怀疑HERV参与一些癌症的发病机制，检测到HERV在生殖细胞肿瘤、前列腺癌和乳腺癌、黑色素瘤、肾细胞癌中的表达。然而，HK 2 RNA，蛋白质和颗粒在癌症中的表达并不能确定HK 2活性在人类癌症病因学中的作用。一些癌症的发病率在艾滋病毒感染中并没有增加，甚至有所下降，如乳腺癌、前列腺癌或结肠癌。我们最近开发了一种新的计算途径程序“望远镜”，它可以使用RNASeq数据集来精确定位HERV转录的染色体上的基因座。在初步研究中，我们已经使用该途径在HIV感染细胞中定位HERV表达，并发现HERV表达的不同染色体模式。我们假设HIV对HERV的再激活刺激特异性识别也在前列腺癌、结肠癌和乳腺癌中表达的HERV的抗HERV免疫，并且这些HIV诱导靶向在乳腺癌、结肠癌或前列腺癌中表达的HERV的HERV特异性免疫应答。我们提出三个目标：目标1：为了确定哪些HERV在前列腺癌、乳腺癌和结肠癌中表达，在有或没有HIV感染的患者中，使用计算途径程序“望远镜”来询问来自医学可用来源的RNASeq数据。目标二：根据NIH资助的ACSR中现有的材料，确定哪些HERV在前列腺癌、乳腺癌和结肠癌中表达，以及有或无HIV感染的患者。目的3：确定前列腺癌、乳腺癌或结肠癌患者、HIV感染或非HIV感染患者的抗HERV免疫应答。在这项提案中，我们的目标是开发和测试假设，源于我们的初步数据，这将验证和扩大的知识HERV表达在前列腺癌，结肠癌和乳腺癌在存在或不存在艾滋病毒感染，并关联特定的HERV表达和特定的抗HERV免疫与癌症免疫监视。