EducationB.S & M.S., Biochemistry, Moscow State University of Education, Moscow, Russia
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
My laboratory studies the molecular mechanisms of innate immune response to radiation-induced stress and involvement of the endogenous retroviruses and retroelements in this response. Even mild radiation doses may induce prolonged or chronic inflammation that disrupts organ functions. This is an important factor of secondary radiation-related disorders, such as vascular abnormalities, neuronal damage, autoimmune diseases and radiation-related cancer. We consider molecular patterns associated with viral infections, such as viral RNAs and proteins as the essential factors that modulate and exacerbate radiation-induced inflammation.
Radiation-induced cellular stress and human endogenous retroviruses
Human endogenous retroviruses (HERVs) constitute 8.3% of our genome. Most of integrated HERV genomes are silenced. However, detection of high levels of HERV-K mRNA, proteins, and even viral particles in a wide range of embryonic cells and cancers suggests that some HERVs may play an essential role in cell differentiation and cancer development. Recent studies revealed transcriptional activation of some retroviral genomes in various cancers and immune cells after exposure to radiation doses. We investigate the effect of gamma radiation on the expression of human endogenous retroviruses and their impact on inflammatory response in various types of immune cells. We found that promoters of certain HERV genomes become permanently activated after the single doses of radiation. Retroviral RNA, as well as some viral proteins, particularly Env (envelope protein), affect innate immune response and can enhance radiation-induced inflammation via the activation of critical pathways. Our ultimate goal is to elucidate the retrovirus-related mechanisms that enhance radiation-induced inflammation and indirect pathogenic effect of radiation on unexposed cells. Our long term goal is to reduce the inflammatory response to ionizing radiation using reprogramming cytokine profile of radiation-activated cells from pro- to anti-inflammatory phenotype via the modulation of expression of endogenous retroelements.
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 noncoding RNAs and mRNA, 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.
Representative publications, projects, and/or deployments
Barclay RA, Schwab A, DeMarino C, Akpamagbo Y, Lepene B, Kassaye S, Iordanskiy S and F. Kashanchi. Exosomes from uninfected cells activate transcription of latent HIV-1. J Biol Chem. 2017 292(28):11682-11701; PMID: 28536264
Akpamagbo YA, DeMarino C, Pleet ML, Schwab A, Rodriguez M, Barclay RA, Sampey G, Iordanskiy S, El-Hage N and F Kashanchi. HIV-1 Transcription Inhibitors Increase the Synthesis of Viral Non-Coding RNA that Contribute to Latency. Curr Pharm Des. 2017; 23(28):4133-4144. PMID: 28641535.
Pleet ML, Mathiesen A, DeMarino C, Akpamagbo YA, Barclay RA, Schwab A, Iordanskiy S, Sampey GC, Lepene B, Nekhai S, Aman MJ and F Kashanchi. Ebola VP40 in Exosomes Can Cause Immune Cell Dysfunction. Front Microbiol. 2018; 9:692.. PMID: 29696006.
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.