HIV, HERV-K and Human Cancer

这项研究将研究HIV Rev在激活人类内源性逆转录病毒方面所起的潜在作用 HIV感染者的家族、Herv-K(HML-2)2型和含有RcRE的细胞基因，以及这是如何 可能会启动一个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，尽管许多已知由于多个突变而处于不活跃状态。HERV-K(HML-2) 家族是最近入侵人类基因组的，也是最活跃的。几份复印件 病毒具有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都很活跃。 而且，它们也被证明在艾滋病毒感染期间被激活。然而，HERV在 尽管由Herv-K(HML-2)病毒表达的调节蛋白已经 已被认为在胚胎发育中作为癌基因和细胞基因的激活剂发挥作用。HERV-K 调节蛋白，Rec，是一种与HERV mRNAs中的Rec反应元件(RcRE)结合的蛋白质，具有 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和HERV-K在HIV感染中的分子相互作用。 具体地说，我们将探索HIV Tat和REV蛋白诱导Herv-K表达的假设 从前病毒复制，导致功能的Rec蛋白的表达。然后，REC可以直接与 在细胞RNA中顺式作用的“RcRE”元件，以促进其核质输出和表达。它是 也有可能REV可以直接与含有RcREs的细胞基因相互作用。这些过程可能会导致 通过表达新的蛋白质亚型来促进肿瘤的发生。 在这项提案中，将开发检测方法来测量功能Rec的表达并鉴定细胞 RNAs，它包含顺式作用序列(细胞RcRE)，直接由Rec或Rev在 转录后水平。基于已知的Rec和Rev蛋白在mRNA调控中的特定作用 在保留内含子的情况下，预计许多诱导的mRNA将代表这种类型的交替 剪接的RNA和编码可能与癌症有关的新的蛋白质亚型。这些活动最初的重点是 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(精原细胞瘤)。HERV-K (HML-2)2型激活在这两种癌症中都得到了很好的证实，而且据报道，它们也是 在艾滋病毒感染者中比例过高。在这项研究的结论中，预计有意义的小说 关于HIVRev与Herv-K和细胞基因相互作用的信息将已经生成，并且 进一步阐明了这些相互作用在癌症发展中的潜在作用。

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.