Immune evasion strategies of Hepatitis C virus (HCV)

Abstract

Standing high level of the innate and adaptive immune resistance, hepatitis C virus (HCV) causes chronically persisting infection in most exposed individuals. Chronic replication is evidence of a multi-layered immune‐evasion program commencing at the time pathogen symmetry and continuing across antigen exposure, effector‐cell function, and antibody recognition and so on. Key signaling nodes in Type I/III IFN induction and response pathways are subverted by viral nonstructural proteins (most notably NS3/4A, NS4B and NS5A), and structural elements of the E1/E2 envelope glycoproteins together with lipaviroparticle configuration minimize sensitivity to neutralizing antibodies. Concurrently, HCV promotes a qualitative defect of cellular immunity through T cell exhaustion, regulatory networks and perturbation of dendritic cell (DC) and NK cell function. In this review, we have integrated the current knowledge of HCV immune evasion mechanisms and how they work together to promote persistence and discuss their implications for vaccine design and immunotherapeutic strategies.

Hepatitis C virus (HCV), a poorly cytopathic single-stranded RNA virus, persists in the majority of individuals who encounter the virus although HCV-specific innate and adaptive immune responses are frequently vigorous, reflecting pathogens with extraordinary mechanisms to elude host immune control. Persistence is organized by a hierarchical program that functions from initial pathogen sensing to effector and antibody-mediated immunity. HCV nonstructural (NS) proteins, mainly NS3/4A, NS4B, and NS5A, inhibit major players of innate immunity signal pathways by PRRs and IFN activators, MAVS, TRIF, STING, and PKR to diminish IFN induction while reprograming antiviral effector responses. Simultaneously, HCV undermines early antiviral control through the circumvention of natural killer cell function and dampening dendritic cell maturation and antigen presentation to generate a tolerogenic 

immune environment. Chronic antigen exposure additionally drives functional exhaustion of virus-specific T cells by inhibitory receptor pathways such as PD-1, curbing effective cellular immunity. At the humoral level, broad glycan shielding and structural flexibility of the E1/E2 viral envelope glycoproteins, packaging with host lipoproteins as lipoviroparticles, and immune evasion through antibody-resistant cell-to-cell transmission provide strong dampening effects on neutralizing antibody responses. Here we provide an overview of current concepts of how these evasion strategies act in concert and redundancy to secure viral persistence, summarized from mechanistic understanding. Knowledge of this global evasion network could have implications in the rational design of HCV vaccines and diagnostic immunotherapies for preventing immune escape and achieving persistent protection.