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. 2019 Apr 25;8(4):376.
doi: 10.3390/cells8040376.

Hepatitis C Virus Infection: Host⁻Virus Interaction and Mechanisms of Viral Persistence

Free PMC article

Hepatitis C Virus Infection: Host⁻Virus Interaction and Mechanisms of Viral Persistence

DeGaulle I Chigbu et al. Cells. .
Free PMC article


Hepatitis C (HCV) is a major cause of liver disease, in which a third of individuals with chronic HCV infections may develop liver cirrhosis. In a chronic HCV infection, host immune factors along with the actions of HCV proteins that promote viral persistence and dysregulation of the immune system have an impact on immunopathogenesis of HCV-induced hepatitis. The genome of HCV encodes a single polyprotein, which is translated and processed into structural and nonstructural proteins. These HCV proteins are the target of the innate and adaptive immune system of the host. Retinoic acid-inducible gene-I (RIG-I)-like receptors and Toll-like receptors are the main pattern recognition receptors that recognize HCV pathogen-associated molecular patterns. This interaction results in a downstream cascade that generates antiviral cytokines including interferons. The cytolysis of HCV-infected hepatocytes is mediated by perforin and granzyme B secreted by cytotoxic T lymphocyte (CTL) and natural killer (NK) cells, whereas noncytolytic HCV clearance is mediated by interferon gamma (IFN-γ) secreted by CTL and NK cells. A host-HCV interaction determines whether the acute phase of an HCV infection will undergo complete resolution or progress to the development of viral persistence with a consequential progression to chronic HCV infection. Furthermore, these host-HCV interactions could pose a challenge to developing an HCV vaccine. This review will focus on the role of the innate and adaptive immunity in HCV infection, the failure of the immune response to clear an HCV infection, and the factors that promote viral persistence.

Keywords: HCV; NK cells; T cells; dendritic cells; immune dysregulation; interferons; viral persistence.

Conflict of interest statement

The authors report no financial or other conflicts of interest.


Figure 1
Figure 1
The replication of hepatitis C (HCV): The virus via its envelope glycoproteins attach to host cellular receptors such as claudin-1, epidermal growth factor receptor (EGFR), scavenger receptor class B type 1 (SRB1), cluster of differentiation (CD81), low density lipoprotein receptor (LDLR), and DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) to attach and subsequently gain entry into host cells. Following attachment, HCV entry occurs via clathrin-mediated endocytosis, wherein HCV undergoes uncoating to release the nucleocapsid into the cytoplasm. HCV RNA is released into the cytoplasm, where it is exposed to host immune machinery. HCV RNA translation via an Internal Ribosome Binding Site (IRES) at the rough endoplasmic reticulum (ER) gives rise to a large polyprotein that undergoes processing into nonstructural and structural proteins. Nonstructural protein NS4B induces the formation of a membranous replication web, where viral RNA replication occurs via the action of RNA-dependent RNA polymerase. The nascent positive sense RNA genome is used for the production of viral proteins, further RNA replication, or the formation of new virions. Utilization of fatty acid pathways along with structural proteins culminate in viral assembly and release.
Figure 2
Figure 2
A host immune response to an HCV infection: The interaction between HCV and hepatocytes induces innate and adaptive immune responses. During an HCV infection of hepatocytes, HCV RNA engages TLR3, RIG-I, and MDA5 on infected hepatocytes as well as TLR7 on pDC to induce the secretion of type I and III interferons. Type I and III IFN inhibit HCV replication and activate NK cells. Activated NK cells produce IFN-γ and TNFα, which induce DC maturation and inhibit HCV replication. Matured DC produce IL-12 that induce the differentiation of CD4 T cells and CD8 T cells into Th1 cells and Cytotoxic T cells, respectively. Additionally, IL-12 and IL-15 secreted by DC activate NK cells. Th1 cells secrete IL-2, IFN-γ, and TNFα. IL-2 induce the proliferation of CD8 T cells, whereas IFN-γ and TNFα inhibit HCV replication without inducing a cytolysis of HCV-infected cells. Furthermore, IFN-γ produced by Th1 cell induce the differentiation of B cells into plasma cells that produce neutralizing antibodies. Finally, perforin and granzyme B produced by CTL and activated NK cells induce the cytolysis of HCV-infected cells.

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