Immune system control of hepatitis C virus infection

Abstract

Hepatitis C virus (HCV) remains a global public health problem even though more than 95% of infections can be cured by treatment with direct-acting antiviral agents. Resolution of viremia post antiviral therapy does not lead to protective immunity and therefore reinfections can occur. Immune cell detection of HCV activates signaling pathways that produce interferons and trigger the innate immune response against the virus, preventing HCV replication and spread. Cells in the innate immune system, including natural killer, dendritic, and Kupffer cells, interact with infected hepatocytes and present viral antigens to T and B cells where their effector responses contribute to infection outcome. Despite the immune activation, HCV can evade the host response and establish persistent infection. Plans to understand the correlates of protection and strategies to activate proper innate and adaptive immune responses are needed for development of an effective prophylactic vaccine that stimulates protective immunity and limits HCV transmission.

Figure 1.. Induction and Evasion of Innate Antiviral Responses by HCV.

HCV RNA structures are detected by cellular RNA sensors. In hepatocytes (left), RIGI and MDA5 recognize 5’ triphosphate RNA, dsRNA, and the long noncoding RNA lncITPRIP-1, respectively, to activate adaptor protein MAVS. MAVS recruits and activates TBK1-regulated phosphorylation of transcription factors IRF3 and NF-κb, resulting in NAP1L1-mediated nuclear translocation and production of type I interferons (IFNB) and type III interferons (IFNL). RIGI and MDA5 signaling are antagonized by HCV proteins (shown in red). HCV NS3 sequesters TBK1; HCV NS5A promotes degradation of NAP1L1; and HCV NS3/4 cleaves ring finger protein 135 (RNF135 or Riplet) and MAVS to prevent IFN expression. Endosomal TLR3 recognizes HCV dsRNA and signals through the adaptor protein TRIF to activate IRF3 hepatoma cell culture experiments. It is not clear whether endocytic uptake of cytoplasmic dsRNA occurs in hepatocytes of HCV-infected livers. HCV NS3/4A cleaves TRIF, impeding IFN signaling. HCV IRES and dsRNA bind PKR to promote or reduce its activity. HCV NS5A stimulates PKR to inhibit translation in immune cells, reducing expression of IFNs. Secreted IFNB and IFNL bind to their respective receptors IFNAR1, IFNAR2, and IFNLR1, IL10RB, expressed on hepatocytes and immune cells (right) to activate JAKs to phosphorylate STAT proteins. STATs form complexes with IRF9 and translocate to the nucleus, where they induce expression of ISGs, which amplify the IFN-mediated, antiviral immune response. HCV core upregulates SOCS3 (an inhibitor of JAK2) and the HCV NS5A protein suppresses STAT1 phosphorylation to impede expression of ISGs. Abbreviations are as follows: TBK1, TANK binding kinase 1; NAP1L1, nucleosome assembly protein 1 like 1; JAK1, Janus kinase 1; STAT, signal transducer and activator of transcription 1; SOCS3, suppressor of cytokine signaling 3; IRF9, interferon regulatory factor 9.

Figure 2.. Adaptive immune responses in spontaneous clearance, persistence, and re-infection of HCV.

(A) Spontaneous clearance: during acute HCV infection (0–6 months), CD4⁺ T cells (Th1 and Tfh cells) activate HCV-specific CD8⁺ T and B cells indirectly (via DCs) or directly (via interactions between CD40 and CD40L). Activated CD8⁺ T cells and B cells enter germinal centers, where they proliferate and differentiate into effector T cells with cytotoxic function or antibody-secreting cells (ASCs), respectively. Cytolytic T cells (CTLs) kill infected hepatocytes, whereas Th1 and Th17 cells release cytokines that promote localized inflammation and potentiate the activities of CTLs. ASCs release antibodies that neutralize autologous HCV. (B) Persistence: activation of B cells and CD8⁺ T cells by CD4⁺ T cells (Th1 and Tfh cells) is limited. Treg cells reduce the activity of CTLs, and mutant viruses escape antibody neutralization and killing by T cells. As viremia persists, constant expression of inhibitory molecules (red) results in T-cell exhaustion (EXT), but some CD8⁺ T cells acquire a memory-like phenotype (TCF1+PD-1+). (C) Re-infection: existing memory CD4⁺ and CD8⁺ T cells and memory B cells (MBCs) are rapidly activated and proliferate upon re-exposure to HCV. Activated, HCV-specific T and B cells can undergo further rounds of affinity maturation in germinal centers and/or rapidly differentiate into effector T cells or ASCs, respectively. Cytotoxic activity and nAbs are increased during secondary HCV infection, leading to faster clearance and expansion of memory T and B cells. (GC = germinal center; mCD4⁺ = memory CD4⁺ + T cell; mCD8⁺ = memory CD8⁺ + T cell; MTL CD8⁺ = memory-like CD8⁺ T cell).