Immune control and failure in HCV infection--tipping the balance

Abstract

Despite the development of potent antiviral drugs, HCV remains a global health problem; global eradication is a long way off. In this review, we discuss the immune response to HCV infection and particularly, the interplay between viral strategies that delay the onset of antiviral responses and host strategies that limit or even eradicate infected cells but also contribute to pathogenesis. Although HCV can disable some cellular virus-sensing machinery, IFN-stimulated antiviral genes are induced in the infected liver. Whereas epitope evolution contributes to escape from T cell-mediated immunity, chronic high antigen load may also blunt the T cell response by activating exhaustion or tolerance mechanisms. The evasive maneuvers of HCV limit sterilizing humoral immunity through rapid evolution of decoy epitopes, epitope masking, stimulation of interfering antibodies, lipid shielding, and cell-to-cell spread. Whereas the majority of HCV infections progress to chronic hepatitis with persistent viremia, at least 20% of patients spontaneously clear the infection. Most of these are protected from reinfection, suggesting that protective immunity to HCV exists and that a prophylactic vaccine may be an achievable goal. It is therefore important that we understand the correlates of protective immunity and mechanisms of viral persistence.

Keywords: B lymphocytes; NK cells; T lymphocytes; immune evasion; innate immunity; interferons.

Figure 1.. Innate recognition of HCV RNA.

These pathways are reviewed in detail in refs. [24, 36]. (A) RIG-I binds HCV RNA, resulting in a change in RIG-I conformation and the activation of E3 ubiquitin ligases (yellow shapes). Ubiquitinated RIG-I may activate MAVS, which forms prion-like aggregates that recruit additional ubiquitin ligases. Activated MAVS forms prion-like aggregates that recruit the E3 ubiquitin ligases TRAF2/5/6 and TRAF3. The ubiquitin ligases catalyze the production of K63 polyubiquitin chains and recruitment of enzymes that activate the downstream IRF3 and NF-κB pathways. The NS3/4A protease of HCV can disable this pathway by cleaving MAVS near its transmembrane domain. ISG15, possibly induced by HCV RNA-stimulated PKR, may inhibit one or more ubiquitination steps. RNF135, ring finger protein 135; TRADD, TNFR type 1-associated death domain; NEMO, NF-κB essential modifier; IKK, IκB kinase. (B) TLR3 recognizes dsRNA within endosomal compartments and signals via the adaptor, TRIF, which recruits ubiquitin-conjugating enzymes, including TRAF3 and -6. These synthesize K63 polyubiquitin, which recruits enzymes that activate the IRF3 and NF-κB transcription factors. The NS3-4A protease of HCV can disable TLR3 signaling by cleaving TRIF. PELI-1, protein pellino homolog 1; TAK, TGF β-activated kinase; TAB, TAK-binding protein.

Figure 2.. T cell responses in acute resolving and chronic HCV infection.

(A) Patterns of viremia (HCV RNA) and liver cell death [alanine aminotransferase (ALT), which is released from damaged hepatocytes] during acute self-limiting HCV infection. (B) CD4⁺ and CD8⁺ T cells respond to multiple HCV epitopes until viremia is cleared and afterward. (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 as a result of exhaustion after loss of CD4⁺ T cell help. CD8⁺ T cells also select for variant virus sequences that escape immune detection.

Figure 3.. Humoral immune responses in acute resolving and chronic HCV infection.

(A) Rapid development of HCV nAb may contribute to spontaneous resolution of infection. Antibodies to HCV structural and nonstructural proteins can be detected by enzyme-linked immunoassay (EIA). Antibody levels may decline after infection is cleared. (B) Slower development of nAb responses may predispose to chronic infection. Antibody to structural and nonstructural proteins is detectable by EIA.

Figure 4.. Tipping the balance?

Many factors contribute to the success of HCV as a pathogen. These include the ability of HCV to delay innate and adaptive immune responses and its strategy of tactics of delay, distraction, disruptions, decoys, and disguises. The infected host can respond with innate mechanisms that limit virus replication and adaptive immune mechanisms that can mediate sterilizing immunity. The outcome of infection is strongly influenced by host genetic polymorphisms and host mechanisms that prevent excessive tissue damage.