Human endogenous retroviruses (HERVs) constitute from 5 to 8% of human genome. Most of integrated HERV genomes are silenced. However, discovery of high levels of HERV-K mRNA, proteins, and even virions in a wide array of cancers has revealed that some HERVs may be playing a role as an etiological agent in cancer itself. HERV-K subgroup HML-2 is involved into the activation of various types of cancer. Recent studies revealed activation of HERV-K and -R transcription in the prostate and breast cancer after standard doses of radiotherapy. Our findings earlier showed, that the radiation doses used for cancer therapy, when applied to the cells latently-infected with another retrovirus, HIV-1, in the context of HIV-related cancer, affected the cell cycle, induced viral transcription and enhanced apoptotic response in the infected cells. The goal of this project is to identify pathogenic effect of radiation-activated integrated retroviruses on the cells, exposed to different irradiation doses, including gamma and X-ray doses used for cancer therapy and neutrons. The mechanism of activation of retroviral promoters, gene expression, translation and secretion of HERV proteins (including exosome-packaged viral products) will be characterized. Impact of extracellular viral RNA and proteins on unexposed cells will also be analyzed. Key HERV RNA and proteins will be tested for their potential to be used as markers of different radiation doses. Various molecular biology techniques, including transcriptomic and proteomic analysis, nanotrap assays, exosome RNA profiling, and cytokine assay will be employed. The ultimate goal of our study is to determine retrovirus-mediated side effects of radiotherapeutic treatment and environmental radiation and find prospective targets and interventions to counteract this influence.
Iordanskiy S, Kashanchi F: Potential of radiation-induced cellular stress for reactivation of latent HIV-1 and killing of infected cells. AIDS Research and Human Retroviruses 32(2): 120-124, 2016
Iordanskiy S, et al: Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells. Virology 485: 1-15, 2015
Tyagi M, Iordanskiy S, et al: Reactivation of Latent HIV-1 Provirus via Targeting Protein Phosphatase-1. Retrovirology 12: 63, 2015
Ionizing radiation; Human endogenous retrovirus; Gene expression; Transcription regulation; Pathogenesis; Radiation marker; Viral RNA; Exosomes; Transcriptomics;