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Review
. 2017;18(7):826-843.
doi: 10.2174/1389450116666150825110532.

Innate and Adaptive Immune Responses in Chronic HCV Infection

Lynn B Dustin  1
Affiliations
Review

Innate and Adaptive Immune Responses in Chronic HCV Infection

Lynn B Dustin. Curr Drug Targets. 2017.

Abstract

Hepatitis C virus (HCV) remains a public health problem of global importance, even in the era of potent directly-acting antiviral drugs. In this chapter, I discuss immune responses to acute and chronic HCV infection. The outcome of HCV infection is influenced by viral strategies that limit or delay the initiation of innate antiviral responses. This delay may enable HCV to establish widespread infection long before the host mounts effective T and B cell responses. HCV's genetic agility, resulting from its high rate of replication and its error prone replication mechanism, enables it to evade immune recognition. Adaptive immune responses fail to keep up with changing viral epitopes. Neutralizing antibody epitopes may be hidden by decoy structures, glycans, and lipoproteins. T cell responses fail due to changing epitope sequences and due to exhaustion, a phenomenon that may have evolved to limit immune-mediated pathology. Despite these difficulties, innate and adaptive immune mechanisms do impact HCV replication. Immune-mediated clearance of infection is possible, occurring in 20-50% of people who contract the disease. New developments raise hopes for effective immunological interventions to prevent or treat HCV infection.

Keywords: Hepatitis C virus; T cell exhaustion; immune response; innate immunity; interferon lambda; neutralizing antibodies.

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Figures

Figure 1
Figure 1
HCV RNA and polyprotein. Conserved RNA structures in the 5’ and 3’ untranslated regions (UTR) are illustrated. The genome has a single long reading frame encoding a viral polyprotein of approximately 3000 amino acids. The polyprotein is processed co- and post-translationally by host and viral proteases to release the three structural proteins, Core, E1, and E2 (labeled in blue) and the seven non-structural proteins (labeled in red).
Figure 2
Figure 2
Innate immune activation by HCV RNA. A) RIG-I binds to PAMPs in HCV RNA and changes its conformation, activating one or more E3 ubiquitin ligases (yellow shapes). Ubiquitinated RIG-I may activate MAVS, which then forms prion-like aggregates that recruit additional ubiquitin ligases. Recent evidence suggests that MAVS on peroxisomes is particularly important for induction of IFNλ. Subsequent ubiquitination steps stimulate recruitment of enzymes that activate the downstream IRF3 and NFκB pathways. HCV’s NS3/4A protease can disable this pathway by cleaving MAVS near its transmembrane domain. B) TLR3 recognizes dsRNA within endosomal compartments, signaling via the adaptor, TRIF. TRIF stimulates ubiquitin-conjugating enzymes, resulting in recruitment of enzymes that activate the IRF3 and NFκB transcription factors. HCV’s NS3-4A protease can disable TLR3 signaling by cleaving TRIF.
Figure 2
Figure 2
Innate immune activation by HCV RNA. A) RIG-I binds to PAMPs in HCV RNA and changes its conformation, activating one or more E3 ubiquitin ligases (yellow shapes). Ubiquitinated RIG-I may activate MAVS, which then forms prion-like aggregates that recruit additional ubiquitin ligases. Recent evidence suggests that MAVS on peroxisomes is particularly important for induction of IFNλ. Subsequent ubiquitination steps stimulate recruitment of enzymes that activate the downstream IRF3 and NFκB pathways. HCV’s NS3/4A protease can disable this pathway by cleaving MAVS near its transmembrane domain. B) TLR3 recognizes dsRNA within endosomal compartments, signaling via the adaptor, TRIF. TRIF stimulates ubiquitin-conjugating enzymes, resulting in recruitment of enzymes that activate the IRF3 and NFκB transcription factors. HCV’s NS3-4A protease can disable TLR3 signaling by cleaving TRIF.
Figure 3
Figure 3
T cell responses in acute resolving (A–B) and chronic (C–D) HCV infection. A) Patterns of viremia (HCV RNA) and liver cell death (alanine aminotransferase, ALT, which is released from damaged hepatocytes) in spontaneous resolution of HCV infection. B) CD4+ and CD8+ T cells respond to multiple HCV epitopes until viremia is cleared and afterwards. C) Patterns of viremia and liver cell death in chronic infection. D) CD4+ and CD8+ T cell responses wane as viremia persists. CD8+ T cells lose function due to exhaustion after loss of CD4+ T cell help. CD8+ T cells also select for variant virus sequences that escape immune detection.
Figure 4
Figure 4
Humoral immune responses in acute resolving (A) and chronic (B) HCV infection. A) Rapid development of HCV-specific nAb may contribute to spontaneous resolution of infection. Ab to HCV structural and non-structural proteins can be detected by enzyme-linked immunoassay (EIA). Ab levels may decline after infection is cleared. B) Slower development of nAb responses may predispose to chronic infection. Ab to structural and non-structural proteins is detectable by EIA.
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