Inhibition of the HCV Core Protein on the Immune Response to HBV Surface Antigen and on HBV Gene Expression and Replication In Vivo

Wenbo Zhu,Chunchen Wu,Liang Cao,Rongjun Pei,Yun Wang,Xinwen Chen,Bo Qin,Mengji Lu,Wanyu Deng,Sung Key Jang

doi:10.1371/journal.pone.0045146

Wenbo Zhu, Chunchen Wu + Show 8 more

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https://doi.org/10.1371/journal.pone.0045146

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Abstract

The hepatitis C virus (HCV) core protein is a multifunctional protein that can interfere with the induction of an immune response. It has been reported that the HCV core protein inhibits HBV replication in vitro. In this study, we test the effect of the HCV core gene on the priming of the immune response to hepatitis B surface antigen (HBsAg) and on the replication of HBV in vivo. Our results showed that the full-length HCV core gene inhibits the induction of an immune response to the heterogeneous antigen, HBsAg, at the site of inoculation when HCV core (pC191) and HBsAg (pHBsAg) expression plasmids are co-administered as DNA vaccines into BALB/c mice. The observed interference effect of the HCV core occurs in the priming stage and is limited to the DNA form of the HBsAg antigen, but not to the protein form. The HCV core reduces the protective effect of the HBsAg when the HBsAg and the HCV core are co-administered as vaccines in an HBV hydrodynamic mouse model because the HCV core induces immune tolerance to the heterogeneous HBsAg DNA antigen. These results suggest that HCV core may play an important role in viral persistence by the attenuation of host immune responses to different antigens. We further tested whether the HCV core interfered with the priming of the immune response in hepatocytes via the hydrodynamic co-injection of an HBV replication-competent plasmid and an HCV core plasmid. The HCV core inhibited HBV replication and antigen expression in both BALB/c (H-2d) and C57BL/6 (H-2b) mice, the mouse models of acute and chronic hepatitis B virus infections. Thus, the HCV core inhibits the induction of a specific immune response to an HBsAg DNA vaccine. However, HCV C also interferes with HBV gene expression and replication in vivo, as observed in patients with coinfection.

Highlights

Hepatitis C virus (HCV) infection causes chronic hepatic inflammation in patients and severe liver diseases, such as liver cirrhosis and hepatocellular carcinoma [1,2]
We demonstrated that co-administration of DNA vaccines expressing the full-length and truncated HCV core gene resulted in the inhibition of an HCV core-specific immune response [29]
We examined the administration of a vector expressing the HCV C on the development of specific immune responses to the hepatitis B virus (HBV) surface antigen and on HBV gene expression and replication in an HBV mouse model using hydrodynamic injection (HI)

Summary

Introduction

Hepatitis C virus (HCV) infection causes chronic hepatic inflammation in patients and severe liver diseases, such as liver cirrhosis and hepatocellular carcinoma [1,2]. 170 million people worldwide are infected with HCV. This has been largely attributed to the inability of the host immune system to clear the initial HCV infection [3,4]. The HCV core protein (C) is an RNA-binding, dimeric, alphahelical protein that participates in the formation of the HCV viral nucleocapsid. The HCV core protein interacts with a variety of cellular proteins to influence host cell functions and can affect innate and adaptive immune pathways [8,9,10]. The HCV core inhibits type I IFN production by interacting with intracellular viral recognition receptors, such as Toll-like receptors and helicases [11], and regulates the function of NF-kB, which is involved in both innate and adaptive immunity [12]. The HCV core protein impairs the in vitro priming, activation and proliferation of T cells [13,14,15,16,17,18,19]

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