Immune responses to HCV and other hepatitis viruses

Abstract

Five human hepatitis viruses cause most of the acute and chronic liver disease worldwide. Over the past 25 years, hepatitis C virus (HCV) in particular has received much interest because of its ability to persist in most immunocompetent adults and because of the lack of a protective vaccine. Here we examine innate and adaptive immune responses to HCV infection. Although HCV activates an innate immune response, it employs an elaborate set of mechanisms to evade interferon (IFN)-based antiviral immunity. By comparing innate and adaptive immune responses to HCV with those to hepatitis A and B viruses, we suggest that prolonged innate immune activation by HCV impairs the development of successful adaptive immune responses. Comparative immunology provides insights into the maintenance of immune protection. We conclude by discussing prospects for an HCV vaccine and future research needs for the hepatitis viruses.

Figure 1. HCV induces and evades innate immune responses in the liver

(A) HCV-infected hepatocytes form clusters (indicated in green) in the infected liver (Wieland et al., 2013), consistent with the cell-to-cell transmission observed in hepatoma cultures (Ramakrishnaiah et al., 2013; Timpe et al., 2008). (B) Specific HCV RNA structures are recognized by PKR, RIG-I and TLR3 in cell culture experiments. PKR and RIG-I signals are transmitted via MAVS, and TLR3 signals are transmitted via TRIF. Downstream activation of kinases, IRF-3 dependent induction of IFN-β, and NF-κB-dependent induction of proinflammatory cytokines such as TNF-α and CXCL10 is abrogated in the presence of HCV NS3-4A, which cleaves both MAVS (Foy et al., 2003) and TRIF (Li et al., 2005). The induction of IFNL1 transcription is indicated by a dotted line because this pathway has been demonstrated in other models (Osterlund et al., 2007) and not yet been confirmed for HCV infection. The secreted interferons bind to their respective receptors, which via activation of the Jak-STAT pathway amplifies the IFN response and induces a large set of ISGs (not shown). IRES, internal ribosomal entry site; dsRNA, double-stranded RNA; PKR, RNA-dependent protein kinase R; RIG-I, retinoic acid-inducible gene 1; TLR3, toll-like receptor 3; MAM, mitochondria-associated endoplasmic reticulum membrane; MAVS, mitochondrial antiviral signaling protein; TBK1, TANK-binding kinase 1; TRIF, Toll/IL-1 receptor domain–containing adapter inducing IFN-β; IRF-3, IFN-regulatory factor 3. (C) HCV persists in the presence of ISGs. IFN-β production is blocked in the upper right hepatocytes due to intracellular expression of HCV NS3-4A. Whether individual hepatocytes transiently express IFN-β and potentially IFN-λ1 in response to HCV RNA, e.g. in the context of an abortive intracellular infection or prior to accumulating sufficient NS3-4A as indicated in the upper left hepatocyte is not known at present. Nonparenchymal cells, e.g. Kupffer cells, pDCs and BDCA3+ mDC2s contribute to the production of ISG-inducing IFNs, which via binding to their respective receptors and activation of the Jak–STAT pathway induce ISG mRNA and proteins in HCV-uninfected hepatocytes (lower part of the figure). Although ISG mRNAs are induced in HCV-infected hepatocytes (indicated in green), HCV persists by phosphorylating and activating PKR. PKR blocks cap-dependent translation of host proteins but not IRES-dependent translation of HCV proteins (see text for details). Continuous exposure to IFN-α increases STAT1 expression in NK cells and results in increased pSTAT1-dependent cytotoxicity (CD107a expression and TRAIL production) and decreased pSTAT4-dependent IFN-γ production (see text for details). KC, Kupffer cell; pDC, plasmacytoid dendritic cell; mDC, myeloid dendritic cell; NK, natural killer cell; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand.

Figure 2. Clinical, virological and immunological course of acute HCV infection

(A) Acute hepatitis C followed by clinical recovery. The incubation phase with high viremia titer and ISG expression occurs during the first 8 weeks of infection. The acute phase is marked by elevated alanine aminotransferase (ALT) levels and the onset of HCV–specific CD4 and CD8 T cell responses around weeks 8 to 12. HCV–specific antibodies are detectable by enzyme immunoassay (ELISA) a few weeks later, but the impact of low titers of strain–specific neutralizing antibodies is still controversial. After spontaneous resolution of acute HCV infection, HCV–specific memory T cell responses remained detectable for decades whereas antibodies disappear from the circulation. (B) Acute hepatitis C followed by chronic infection. HCV RNA titers decrease 2–3 log₁₀ after the acute phase of hepatitis C and remain relative stable in the chronic phase. Selection of HCV escape mutants is mostly driven by T cells in the acute and early chronic phases of infection, and by increasing titers of broadly targeted neutralizing antibodies in the chronic phase. The intensity of the shaded background indicates the degree of intrahepatic inflammation in the different phases of hepatitis. (C) Adaptive immune responses associated with differential outcome of acute HCV infection. A strong and maintained CD4 T cell response appears to be a critical factor for the outcome of acute HCV infection. In its presence, HCV–specific CD8 T cell populations with an initially “stunned” phenotype acquire multiple effector functions (upper panel). In the absence or loss of a strong CD4 T cell response, CD8 T cells develop exhausted phenotypes, which are attributed to chronic antigen-specific stimulation. Those CD8 T cells that target HCV escape variants remain functional with a memory phenotype in the chronic phase of infection (see text for details). Treg, regulatory T cell.

Figure 3. Conditions for T cell-mediated immune protection upon HCV re-infection

(A) Clearance of a primary HCV infection is associated with strong T cell responses. A secondary HCV infection results in lower HCV titers and more rapid viral clearance. An early memory T cell recall response is detectable in both liver and blood. (B) Depletion of CD4 T cells in chimpanzees prior to secondary HCV infection results in weak recall responses, incomplete T-cell mediated control of viremia and emergence of MHC class I escape mutations. Chronic infection ensues. (C) T cell responses that are induced by repeated exposure to trace amounts of HCV, in the absence of quantifiable systemic viremia and seroconversion (“subinfectious HCV exposure”), do not confer immune protection upon HCV re-infection. The absence of immune protection is associated with an expansion of Treg cells during subinfectious HCV exposure and subsequent HCV challenge. The intensity of the shaded background indicates the degree of intrahepatic inflammation in the different phases of hepatitis.