HIV, HERV-K and Human Cancer

HIV、HERV-K 和人类癌症

基本信息

批准号：
10132254
负责人：
MARIE-LOUISE HAMMARSKJOLD
金额：
$ 40.38万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132254
关键词：
Address Aggressive course Alternative Splicing Binding Binding Proteins Biological Assay Cancer Etiology Cells Cis-Acting Sequence Development Elements Embryonic Development Endogenous Retroviruses Etiology Family Gene Expression Gene Proteins Genes Germ Cell Cancers Germ cell tumor HIV HIV Infections HIV Seropositivity Human Human Genome Human immunodeficiency virus test Immune System Diseases Individual Inflammation Introns Invaded Lead Malignant Neoplasms Measures Mediating Melanoma Cell Messenger RNA Mutation Normal Cell Oncogenes Oncogenic Oncoproteins Patients Peripheral Blood Mononuclear Cell Play Process Protein Isoforms Proteins Publications Publishing RNA RNA Binding Regulation Reporter Reporting Resources Response Elements Role Seminoma Structure System Testing Tissues Translating Translations Virus base cancer cell cancer risk cancer type design experimental study genetic regulatory protein mRNA Expression melanoma novel programs response rev Genes rev Protein tat Genes transcriptome sequencing tumor tumorigenesis vector

项目摘要

This study will examine the potential role that HIV Rev plays in activating the human endogenous retrovirus family, HERV-K (HML-2) type 2 and cellular genes containing RcREs in HIV-infected individuals, and how this might initiate a program of gene expression leading to oncogenesis. Endogenous retroviruses constitute 8% of the human genome, though many are known to be inactive due to multiple mutations. The HERV-K (HML-2) family were the most recent to invade the human genome and are the most active. Several copies of these viruses retain the capacity for expression of structural as well as regulatory proteins. Many recent studies have indicated that these viruses are active in several different types of human cancer and they also have been shown to be activated during HIV infection. However, a direct role for HERVs in oncogenesis remains unknown, although regulatory proteins expressed by the HERV-K (HML-2) viruses have been proposed to function as oncogenes and as activators of cellular genes in embryogenesis. The HERV-K regulatory protein, Rec, is a protein that binds to Rec Response elements (RcREs) in HERV mRNAs with retained introns to promote their export and expression. This is analogous to the role of Rev and RRE in HIV infection. The proposed experiments will analyze HIV and HERV-K molecular interactions in HIV infection. Specifically, we will explore the hypothesis that HIV Tat and Rev proteins induce the expression of HERV-K from proviral copies, leading to the expression of functional Rec proteins. Rec could then directly interact with cis-acting “RcRE” elements in cellular RNAs to promote their nucleo-cytoplasmic export and expression. It is also possible that Rev may directly interact with cellular genes containing RcREs. These processes could lead to oncogenesis through expression of new protein isoforms. In this proposal, assays will be developed to measure functional Rec expression and to identify cellular RNAs, which contain cis-acting sequences (cellular RcREs),that are directly regulated by Rec or Rev at the posttranscriptional level. Based on the known specific role of Rec and Rev proteins in the regulation of mRNA with retained introns, it is expected that many of the induced mRNAs will represent this type of alternatively spliced RNA and encode novel protein isoforms that may be involved in cancer. The initial focus of these studies will be in two types of human cancer: malignant melanoma and germ cell cancer (seminoma). HERV-K (HML-2) type 2 activation is well established in both of these cancers and they also have been reported to be over-represented in HIV infected individuals. At the conclusion of this study, it is expected that significant novel information about HIVRev interactions with HERV-K and cellular genes will have been generated, and the potential role of these interactions in cancer development further elucidated.

这项研究将探讨 HIV Rev 在激活人类内源性逆转录病毒中的潜在作用家族、HERV-K (HML-2) 2 型和 HIV 感染者中含有 RcRE 的细胞基因，以及这如何发生可能启动导致肿瘤发生的基因表达程序，内源性逆转录病毒占 8%。人类基因组，尽管已知许多 HERV-K (HML-2) 因多重突变而失活。家族是最近侵入人类基因组并且是最活跃的几个拷贝。病毒保留表达结构蛋白和调节蛋白的能力。最近的许多研究表明，这些病毒在几种不同类型的人类癌症中具有活性它们也被证明在 HIV 感染期间被激活，然而，HERV 在感染中发挥着直接作用。尽管 HERV-K (HML-2) 病毒表达的调节蛋白已经 HERV-K 已被认为在胚胎发生过程中充当癌基因和细胞基因激活剂。调节蛋白 Rec 是一种与 HERV mRNA 中的 Rec 响应元件 (RcRE) 结合的蛋白保留内含子以促进其输出和表达，这类似于 Rev 和 RRE 在 HIV 中的作用。感染。拟议的实验将分析 HIV 感染中的 HIV 和 HERV-K 分子相互作用。具体来说，我们将探讨 HIV Tat 和 Rev 蛋白诱导 HERV-K 表达的假设来自原病毒拷贝，导致功能性 Rec 蛋白的表达，然后可以直接与 Rec 相互作用。细胞 RNA 中的顺式作用“RcRE”元件可促进其核质输出和表达。 Rev 也有可能直接与含有 RcRE 的细胞基因相互作用，这些过程可能导致。通过表达新的蛋白质亚型来促进肿瘤发生。在本提案中，将开发检测方法来测量功能性 Rec 表达并识别细胞 RNA，包含顺式作用序列（细胞 RcRE），直接受 Rec 或 Rev 调节基于 Rec 和 Rev 蛋白在 mRNA 调节中的已知特定作用。由于保留了内含子，预计许多诱导的 mRNA 将代表这种类型的替代性剪接的RNA并编码可能与癌症有关的新型蛋白质亚型。研究将针对两种类型的人类癌症：恶性黑色素瘤和生殖细胞癌（HERV-K）。 (HML-2) 2 型激活在这两种癌症中已得到充分证实，并且也有报道称它们是在这项研究的结论中，预计会出现重大的新发现。有关 HIVRev 与 HERV-K 和细胞基因相互作用的信息将会生成，并且这些相互作用在癌症发展中的潜在作用得到了进一步阐明。