The Immunogenicity in Mice of HCV Core Delivered as DNA Is Modulated by Its Capacity to Induce Oxidative Stress and Oxidative Stress Response

Juris Jansons, Irina Sominskaya, Natalia Petrakova, Elizaveta S. Starodubova, Olga A. Smirnova, Ekaterina Alekseeva, Ruta Bruvere, Olesja Eliseeva, Dace Skrastina, Elena Kashuba, Marija Mihailova, Sergey N. Kochetkov, Alexander V. Ivanov, Maria G. Isaguliants (Coresponding Author)

Research output: Contribution to journalArticlepeer-review

Abstract

HCV core is an attractive HCV vaccine target, however, clinical or preclinical trials of core-based vaccines showed little success. We aimed to delineate what restricts its immunogenicity and improve immunogenic performance in mice. We designed plasmids encoding full-length HCV 1b core and its variants truncated after amino acids (aa) 60, 98, 152, 173, or up to aa 36 using virus-derived or synthetic polynucleotides (core191/60/98/152/173/36_191v or core152s DNA, respectively). We assessed their level of expression, route of degradation, ability to trigger the production of reactive oxygen species/ROS, and to activate the components of the Nrf2/ARE antioxidant defense pathway heme oxygenase 1/HO-1 and NAD(P)H: quinone oxidoreductase/Nqo-1. All core variants with the intact N-terminus induced production of ROS, and up-regulated expression of HO-1 and Nqo-1. The capacity of core variants to induce ROS and up-regulate HO-1 and Nqo-1 expression predetermined their immunogenicity in DNA-immunized BALB/c and C57BL/6 mice. The most immunogenic was core 152s, expressed at a modest level and inducing moderate oxidative stress and oxidative stress response. Thus, immunogenicity of HCV core is shaped by its ability to induce ROS and oxidative stress response. These considerations are important in understanding the mechanisms of viral suppression of cellular immune response and in HCV vaccine design.
Original languageEnglish
Article number 208
JournalCells
Volume8
Issue number3
DOIs
Publication statusPublished - 28 Feb 2019

Keywords

  • Hepatitis C virus
  • nucleocapsid (core)
  • DNA-immunization
  • oxidative stress
  • cellular immune response
  • predictive marker

Field of Science

  • 3.1 Basic medicine
  • 3.2 Clinical medicine

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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