Sergey Iordanskiy, Ph.D.
Sergey Iordanskiy, Ph.D.
Name: Sergey Iordanskiy, Ph.D.
Molecular biology of retroviruses and host genomes; Effect of cellular stress on virus latency and replication; Exosomes in intercellular communication and cytopathogenesis.
Lentiviral vectors for delivery and expression of genome editing tools; Coinfection of HIV and human blood parasites.
Ph.D., Cellular Biology, Moscow State University of Education & Ivanovsky Research Institute of Virology, Russian Academy of Medical Sciences
Postdoctoral Training, Molecular Biology of AIDS, Picower Institute for Medical Research, Manhasset, NY
Postdoctoral Training, Molecular Virology, George Washington University, Washington, DC
Radiation-induced cellular stress and human endogenous retroviruses
Human endogenous retroviruses (HERVs) constitute from 5 to 9% of human genome. Most of integrated HERV genomes are silenced. However, detection of high levels of HERV-K mRNA, proteins, and even virions in a wide range of cancers suggests that some HERVs may play an essential role in cancer development. HERV-K subgroup HML-2 is involved into the activation of various types of cancer. Recent studies revealed dramatic increase of HERV-K and -R transcription in the prostate, breast and colon cancer after standard doses of radiotherapy. Our studies of the effect of radiation doses used for cancer therapy on the cells latently-infected with another retrovirus, HIV-1, in the context of HIV-related cancer, revealed inappropriate entry and arrest at S phase of the cell cycle, induction of viral transcription and enhanced apoptotic response predominantly in the infected cells. We examine pathogenic effect of integrated retroviruses in the cells, exposed to different irradiation doses, including X-ray and gamma doses used for cancer therapy and neutrons. We focus on the mechanism of activation of retroviral promoters, gene expression, translation and secretion of HERV proteins using chromatin immunoprecipitation, transcriptomic and proteomic analysis. Important part of our study is analysis of the impact of extracellular viral RNA, proteins and likely released HERV virions on unexposed cells. Another aspect of our study is testing of key HERV RNA and proteins for their potential to be used as biomarkers of different radiation doses. Our ultimate goal is to determine retrovirus-mediated side effects of radiotherapeutic treatment and environmental radiation and to find prospective targets and interventions to counteract this influence.
Exosomes in cytopathogenesis and intercellular communications within context of radiation-induced stress.
Initially small extracellular vesicles, exosomes, were thought to be a mechanism for discarding unwanted cellular material. However, in recent years, numerous evidence has indicated the role of exosomes in intercellular communication and the progression of various pathologies, including cancer and multiple neurodegenerative disorders. Exosomes are cell-derived vesicles that are present in all biological fluids and are capable of carrying RNAs and proteins which can be exchanged from cell-to-cell. Existing data indicate that exosomes and their cargo play crucial roles in communicating of radiation-induced and bystander cells with the result related to DNA damage and cell pathogenesis. We recently demonstrated multiple pathogenic effects of exosomes from the cells containing integrated retroviral genomes, such as human T lymphotropic virus 1 (HTLV-1) and HIV-1 on naïve cells. These effects were enhanced by the exposure of producing cells to ionizing radiation. Current research in our laboratory is focused on the analysis of host-cellular and viral cargo in the exosomes released from the radiation-exposed cells. We also investigate how non radiation-exposed cells respond to exosome-mediated effect of radiation in the context of radiotherapy and environmental radiation. Potential outcomes include understanding of the functions of exosome-packaged micro- and mRNAs, viral and host proteins in recipient cells and their pathogenic impact that is related to radiation. Identification of exosome-incorporated biomarkers of radiation doses is also part of this study.
Our laboratory is involved in collaborative projects with George Washington University (Paul Brindley Lab) and Massachusetts Institute of Technology (Kevin Esvelt Lab). These studies are related to coinfection of HIV and human blood fluke Schistosoma mansoni and S. hematobium and the use of HIV-based lentiviral vectors for delivery of gene editing tools within the context of Gene Drive strategy.
- Suttiprapa S, Rinaldi G, Tsai IJ, Mann VH, Dubrovsky L, Yan HB, Holroyd N, Huckvale T, Durrant C, Protasio AV, Pushkarsky T, Iordanskiy S, Berriman M, Bukrinsky MI and PJ Brindley, HIV-1 Integrates Widely throughout the Genome of the Human Blood Fluke Schistosoma mansoni. PLoS Pathog. 2016 Oct 20;12(10):e1005931.
- Santos S, Obukhov Y, Nekhai S, Pushkarsky T, Brichacek B, Bukrinsky M and S Iordanskiy. Cellular minichromosome maintenance complex component 5 (MCM5) is incorporated into HIV-1 virions and modulates viral replication in the newly infected cells, Virology. 2016 Oct;497:11-22.
- Iordanskiy S and F Kashanchi, Potential of radiation-induced cellular stress for reactivation of latent HIV-1 and killing of infected cells. AIDS Res Hum Retroviruses. 2016 32(2):120-124.
- Sampey G, Saifuddin M, Schwab A, Barclay R, Punya S, Chung M-Y, Hakami RM, Asad Zadeh M, Lepene B, Klase ZA, El-Hage N, Young M, Iordanskiy S and F Kashanchi, Exosomes from HIV-1 infected cells stimulate production of pro-inflammatory cytokines through TAR RNA. J Biol Chem. 2016 291(3):1251-1266.
- Iordanskiy S, Van Duyne R, Sampey GC, Woodson CM, Fry K, Saifuddin M, Guo J, Wu Y, Romerio F and F Kashanchi, Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells. Virology 2015, 485:1–15.
- Guendel I, Iordanskiy S, Van Duyne R, Kehn-Hall K, Saifuddin M, Das R, Jaworski E, Sampey G, Senina S, Shultz L, Narayanan A, Chen H, Lepene B, Zeng C, and F. Kashanchi, Novel neuroprotective GSK-3β inhibitor restricts Tat-mediated HIV-1 replication. J Virol 2014, 88(2): 1189-1208
- Narayanan A, Iordanskiy S, Das R, Van Duyne R, Santos S, Jaworski E, Guendel I, Sampey G, Gerhart E, Iglesias-Ussel M, Popratiloff A, Hakami R, Kehn-Hall K, Young M, Subra C, Gilbert C, Bailey C, Romerio F and F. Kashanchi, Exosomes derived from HIV-1 infected cells contain TAR RNA. J Biol Chem. 2013 288(27): 20014-20033.
- Santos S, Obukhov Y, Nekhai S, Bukrinsky M and S Iordanskiy, Virus-producing cells determine the host protein profiles of HIV-1 virion cores. Retrovirology. 2012, 9:65.
- Iordanskiy S, Berro R, Altieri M, Kashanchi F. and M. Bukrinsky, Intracytoplasmic maturation of the human immunodeficiency virus type 1 reverse transcription complexes determines their capacity to integrate into chromatin. Retrovirology 2006. 3: 4
- Iordanskiy S, Zhao Y, DiMarzio P, Agostini I, Dubrovsky L, and M. Bukrinsky, Heat-shock protein 70 exerts opposing effects on Vpr-dependent and Vpr-independent HIV-1 replication in macrophages. Blood. 2004. 104: 1867-1872.