Hypervariable Region 1 in Envelope Protein 2 of Hepatitis C Virus: A Linchpin in Neutralizing Antibody Evasion and Viral Entry.

Jannick Prentoe,Jens Bukh

doi:10.3389/fimmu.2018.02146

Jannick Prentoe, Jens Bukh

Open Access

https://doi.org/10.3389/fimmu.2018.02146

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Abstract

Chronic hepatitis C virus (HCV) infection is the cause of about 400,000 annual liver disease-related deaths. The global spread of this important human pathogen can potentially be prevented through the development of a vaccine, but this challenge has proven difficult, and much remains unknown about the multitude of mechanisms by which this heterogeneous RNA virus evades inactivation by neutralizing antibodies (NAbs). The N-terminal motif of envelope protein 2 (E2), termed hypervariable region 1 (HVR1), changes rapidly in immunoglobulin-competent patients due to antibody-driven antigenic drift. HVR1 contains NAb epitopes and is directly involved in protecting diverse antibody-specific epitopes on E1, E2, and E1/E2 through incompletely understood mechanisms. The ability of HVR1 to protect HCV from NAbs appears linked with modulation of HCV entry co-receptor interactions. Thus, removal of HVR1 increases interaction with CD81, while altering interaction with scavenger receptor class B, type I (SR-BI) in a complex fashion, and decreasing interaction with low-density lipoprotein receptor. Despite intensive efforts this modulation of receptor interactions by HVR1 remains incompletely understood. SR-BI has received the most attention and it appears that HVR1 is involved in a multimodal HCV/SR-BI interaction involving high-density-lipoprotein associated ApoCI, which may prime the virus for later entry events by exposing conserved NAb epitopes, like those in the CD81 binding site. To fully elucidate the multifunctional role of HVR1 in HCV entry and NAb evasion, improved E1/E2 models and comparative studies with other NAb evasion strategies are needed. Derived knowledge may be instrumental in the development of a prophylactic HCV vaccine.

Highlights

It is estimated that at least 2 million people become infected with hepatitis C virus (HCV) every year [1]
The development of HCV pseudo-particles (HCVpp) and HCVcc models [13, 14, 22,23,24], as well as the advent of novel tools, such as comprehensive panels of monoclonal antibodies with non-overlapping E1/envelope protein 2 (E2) epitopes [80,81,82,83,84,85,86,87,88,89,90,91], have facilitated an increasing number of studies that improve understanding of the role of hypervariable region 1 (HVR1) in important aspects of the HCV life cycle, immune evasion and viral entry
It was since shown that the animals had not raised neutralizing antibodies (NAbs) and, that the chimpanzee that cleared acute infection with HVR1-deleted HCV could be chronically infected with the homologous virus following re-challenge [133]

Summary

Introduction

It is estimated that at least 2 million people become infected with hepatitis C virus (HCV) every year [1]. The development of HCVpp and HCVcc models [13, 14, 22,23,24], as well as the advent of novel tools, such as comprehensive panels of monoclonal antibodies with non-overlapping E1/E2 epitopes [80,81,82,83,84,85,86,87,88,89,90,91], have facilitated an increasing number of studies that improve understanding of the role of HVR1 in important aspects of the HCV life cycle, immune evasion and viral entry.

Results

Conclusion