HIV, HERV-K and Human Cancer

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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.