Innate Immune Response to HCV

The innate immune response to HCV is responsible for the activation of cytokines such as interferon (IFN) which activate antiviral proteins that inhibit the replication of the virus while the adaptive immune response to HCV neutralizes viral particles and destroys infected cells (Thimme et al., 2006). Studies of HCV infected chimpanzees that eliminate the virus without the specific T-cell immune response suggest that, in some cases, the innate immune response might be sufficient to destroy the infection (Lloyd et al., 2007).
The RNA of HCV is recognized by the innate immune response through the Toll-like receptor which responds with the production of IFN-1α and IFN-1β (Mizukoshi and Rehermann, 2001 and Dustin and Rice, 2007). IFN-1 stimulates the nitric oxide synthase enzyme that is expressed in hepatocytes and macrophages as the isoform inducible nitric oxide synthase (Samuel, 2001). Patients with HCV who are treated with IFN present higher levels of inducible nitric oxide synthase, which have been correlated with lower serum levels of alanine aminotransferase (Taylor et al., 2000).
In addition, IFN-1 induces the production of various proteins such as protein kinase (PKR), 2’,5’-oligoadenylate synthetase (OAS) and the Mx protein (Taylor et al., 2000). These proteins are responsible for the expression of the genes that inhibit the replication of this virus within hepatocytes in an attempt to destroy the infection (Pawlotsky, 2004 and Thimme et al., 2006). When IFN bonds with the IFN receptor on the surface of the infected cell, it activates the Janus kinase, which induces phosphorylation of cytoplasmic proteins known as signal transducers and activators of transcription (STATs), specifically STAT 1 and STAT 2. The STATs form a dimer that directs itself to the cell nucleus where it forms a complex with the p48 protein, which is a stimulation factor for IFN-stimulated gene factor 3. That complex bonds with the IFN-stimulated response element ISRE, which is an RNA-polymerase promoter complex, and there is a stimulus of the genes responsible for the production of antiviral response proteins and of major histocompatibility complex (MHC) proteins (Taylor et al., 2000).
Some individuals present genetic alterations in the STATs or in the Janus kinase that would impede the formation of antiviral proteins (Tan and Katze, 2001).
Various viral proteins have shown a capacity to escape the effect of IFN, as evidenced by the high rate of resistance to treatment with IFN-α seen among individuals with hepatitis C (Taylor et al., 2000 and Tan and Katze, 2001).
There are various characteristics of HCV that allow it to evade the innate immune response:
1- The viral replication complex appears to be composed of a membrane that is highly resistant to in vitro proteases and nucleases, which protects HCV from detection by the innate immune response (Thimme et al., 2006).
2- The HCV core protein interacts with diverse cell factors, including the tumor necrosis factor (TNF) receptor, which decreases the cytolytic activity of T cells (Chen et al., 1997).
3- Core proteins impede the antiviral activity of IFN, as do NS3/4A and NS5A proteins (Thimme et al., 2006).
4- The NS3/4A proteins can impede the recognition of the Toll-like receptor (Dustin and Rice, 2007).
5- The NS5A and E2 proteins can bind to PKR, thereby blocking its activity (Dustin and Rice, 2007).
6- Multiple mutations in the IFN-sensitivity-determining region (ISDR) modify the NS5A region, which inhibits the phosphorylation of PKR, thereby impeding its antiviral activity (Tan and Katze, 2001).
7- The E2 region of HCV contains a sequence of eight amino acids identical to those of PKR, and this sequence is more common in genotype 1 than in genotypes 2 and 3, which probably accounts for the fact that individuals infected with genotype 1 present greater resistance to treatment with IFN (Taylor et al., 2000).
8- Mutations in the ISDR sequence of NS5A suppress the antiviral action of OAS.
9- Levels of this protein are lower in nonresponders to treatment with IFN (Taylor et al., 2000).
The liver cell populations that participate in the innate immune response are the natural killer (NK) cells, NK T cells, Kupffer cells and dendritic cells (Dustin and Rice, 2007). The NK cells respond minutes or hours after HCV infection by polarizing of the granules in the direction of the infected cells as well as by releasing perforins that fragment the nuclei of infected cells and induce apoptosis (Rhermann and Chisari, 2000). They inhibit viral replication with the production of IFN gamma (IFN-γ), which recruits intrahepatic inflammatory cells and stimulates the T-helper 1 (Th1) response (Janeway et al., 2007), thereby inducing the necrosis or apoptosis of the HCV infected cell (Winnock et al., 1993).
Studies suggest that HCV inhibits receptor genes in the activation of NK cells, decreasing the activity of these cells by reducing their number and function in chronically infected individuals (Thimme et al., 2006). The NK cells also have the capacity to increase the functions of dendritic cells in the presence of hepatic cells, although that capacity is impaired in NK cells derived from patients with chronic hepatitis C, in which the production of interleukin (IL)-10 and transforming growth factor beta (TGF-β) can inhibit the activity of dendritic cells (Jinushi et al., 2004).
After HCV enters the host cell, the binding of the E2 glycoprotein with the CD81 receptor of NK cells inhibits the function of the NK cells (Crotta et al., 2002 and Pawlotsky, 2004), which alters the immune response to HCV infection. The E2 glycoprotein also inhibits cytotoxicity and the production of IFNγ by NK cells (Thimme et al., 2006). Various studies have suggested that the failure of dendritic cells to recognize HCV contributes to the persistence of hepatitis C (Bain et al., 2001; Sarobe et al., 2002; Jinushi et al., 2004 and Longman et al., 2004).