Neutralizing antibodies and pathogenesis of hepatitis C virus infection

Abstract

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The interplay between the virus and host innate and adaptive immune responses determines the outcome of infection. There is increasing evidence that host neutralizing responses play a relevant role in the resulting pathogenesis. Furthermore, viral evasion from host neutralizing antibodies has been revealed to be an important contributor in leading both to viral persistence in acute liver graft infection following liver transplantation, and to chronic viral infection. The development of novel model systems to study HCV entry and neutralization has allowed a detailed understanding of the molecular mechanisms of virus-host interactions during antibody-mediated neutralization. The understanding of these mechanisms will ultimately contribute to the development of novel antiviral preventive strategies for liver graft infection and an urgently needed vaccine. This review summarizes recent concepts of the role of neutralizing antibodies in viral clearance and protection, and highlights consequences of viral escape from neutralizing antibodies in the pathogenesis of HCV infection.

Figure 1

Strategies of viral evasion during Hepatitis C virus (HCV) infection. HCV has adapted multiple mechanisms to escape host immunity. The low-fidelity HCV RNA polymerase NS5B introduces point mutations to generate a genetic diversity within the quasispecies in an infected host. Many of the viable variants cluster in high-variability regions (e.g., HVR1) of the glycoprotein sequences, which can contribute to differential binding and usage of HDL and SR-BI of different variants, providing flexibility for adaptation against host humoral immunity. Glycosylation sites conceal important functional domains of E2 by forming a glycan shield that reduces the viral immunogenicity and the access of the epitopes to nAbs (reviewed in [68]). Additionally, the action of nAbs may also be disturbed by the presence of interfering antibodies. Another way of escaping neutralizing antibodies is by avoiding the circulation altogether, by dissemination via cell-to-cell transmission. HDL: High Density Lipoprotein ; HVR1: Hypervariable Region 1; nAbs: neutralizing Antibodies