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

doi:10.3390/cells8030208

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.

Highlights

Hepatitis C virus (HCV) nucleocapsid is the most conserved HCV gene [1,2,3]
In a mouse study of the oxidative stress and oxidative stress response to a panel of genes encoding HIV-1 reverse transcriptase (RT) of varying immunogenicity, we showed that IFN-γ response induced in immunization of mice with RT DNA correlated with the capacity of encoded RT variants to induce reactive oxygen species (ROS) and activate the transcription of antioxidant response element (ARE)-dependent phase II detoxifying enzyme genes [87]
Our study demonstrated that cellular immunogenicity of HCV core is shaped by its ability to induce ROS and oxidative stress response

Summary

Introduction

Hepatitis C virus (HCV) nucleocapsid (core) is the most conserved HCV gene [1,2,3]. Its quasispecies demonstrate unique homogeneity within the patients [4]. No genetic mutations have been detected in any of the CTL-epitope encoding core gene regions despite detectable cellular responses [1]. Conservation of HCV core and its vital role for the virus make it attractive as an HCV vaccine component. Several studies observed that transient expression of HCV core interferes with the induction of cellular immune responses against co-delivered genes [15,16]. In lines with these findings, mice transgenic for HCV core demonstrated significantly diminished T-lymphocyte responses compared to their non-transgenic littermates [17], and could not adequately respond to viral infections [18,19]

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