Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence

Abstract

Since the identification of the hepatitis C virus (HCV) 20 years ago, much progress has been made in our understanding of its life cycle and interaction with the host immune system. Much has been learned from HCV itself, which, via decades of coevolution, gained an intricate knowledge of host innate and adaptive immune responses and developed sophisticated ways to preempt, subvert, and antagonize them. This review discusses the clinical, virological, and immunological features of acute and chronic hepatitis C and the role of the immune response in spontaneous and treatment-induced HCV clearance.

Figure 1. HCV genome organization.

(A) The single-stranded RNA genome encodes a long open reading frame (ORF) flanked by 2 UTRs, which contain signals for viral protein and RNA synthesis and the coordination of both processes. Translation is initiated through an internal ribosomal entry site (IRES) in the 5’ UTR. U, uridine; C, cytidine. (B) The translated polyprotein is cotranslationally and posttranslationally processed by cellular and viral proteases. Numbers below the polyprotein indicate the amino acid positions of the cleavage sites. (C) Function of the resulting 10 structural and nonstructural proteins. A frameshift (F) protein is translated from a short alternate reading frame (ARF). Figure modified with permission from Nature Reviews Immunology (S23).

Figure 2. HCV attenuates innate immune responses.

(A) Hepatocytes sense HCV dsRNA structures via pattern recognition receptors RIG-I and TLR3. These receptors activate via their adaptor molecules IPS-1 and TRIF, respectively, NF-κB, and the downstream kinases IKKε and TNF receptor–associated factor family member–associated NF-κB activator–binding kinase–1 (TBK1). IKKε and TBK1 phosphorylate the transcription factor IRF3, which dimerizes, translocates to the nucleus, and activates IFN-β gene transcription in synergy with NF-κB. HCV NS3/4A cleaves the adapter molecules TRIF and IPS-1, thereby blocking TLR3 and RIG-I signaling. (B) Binding of IFN-β to the IFN-α/β receptor (IFNAR-1 and -2) activates the JAK/STAT pathway. Specifically, TYK2 and JAK1 kinase activation results in the generation, phosphorylation, and assembly of the trimeric ISGF3 transcription factor complex, which consists of a STAT1–STAT2 heterodimer and IRF9. This complex translocates to the nucleus, binds to IFN-stimulated response elements (ISREs) within the promoter/enhancer region of ISGs and induces 2′-5′ OAS, PKR, and IRF7 production. HCV core interferes with the JAK/STAT pathway by inducing SOCS1/3 and by inhibiting STAT1 phosphorylation. The HCV polyprotein induces protein phosphatase 2A (PP2A), which interferes with STAT1 methylation, thereby increasing the binding of STAT1 to protein inhibitor of activated STAT1 (PIAS). STAT1/PIAS interaction impairs the binding of the ISGF3 complex to the IFN-stimulated response element and blocks the transcription of ISGs. HCV E2 and HCV NS5A inhibit the function of several ISGs (see text for details).

Figure 3. Schematic of the clinical, immunological, and virological course of acute HCV infection.

(A) Acute hepatitis C followed by clinical recovery. The incubation phase occurs during the first 2–3 months after infection. The acute phase is marked by increased ALT levels in most patients, although only about 20%–30% develop clinical symptoms such as jaundice. ALT elevations coincide with the onset of HCV-specific T cell responses in the liver, and these responses are detectable in the blood by proliferation and cytokine assays. HCV-specific antibodies are detectable by enzyme immunoassay (EIA) at this time, but the presence of transient, strain-specific neutralizing antibodies is still controversial. After clearance of HCV, antibody titers decrease and may eventually become undetectable. HCV-specific T cells remain detectable in the blood, and in vitro recall responses to HCV antigens remain indicators of previous infection and recovery. (B) Chronically evolving acute hepatitis C. Chronic HCV infection is characterized by relatively stable HCV RNA levels, which are about 2–3 log₁₀ lower than in the acute phase and do not vary by more than 1 log₁₀ during the chronic phase. The titers of HCV-specific antibodies, including those of neutralizing antibodies against multiple HCV strains, increase during chronic hepatitis. HCV-specific T cell reactivity decreases over time, and in vitro recall responses to HCV antigens are typically weak to undetectable. Figure modified with permission from Seminars in Liver Disease (S24).