scholarly journals Structure of the hepatitis C virus E1E2 glycoprotein complex

2021 ◽  
Author(s):  
Alba Torrents de la Pena ◽  
Kwinten Sliepen ◽  
Lisa Eshun-Wilson ◽  
Maddy Newby ◽  
Joel D. Allen ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Hydrophobic Interactions ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Fusion Glycoprotein

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma in humans, and afflicts more than 58 million people worldwide. The HCV envelope E1 and E2 glycoproteins are essential for viral entry and infection, and comprise the primary antigenic target for neutralizing antibody responses. The molecular mechanisms of E1E2 assembly, as well as how the E1E2 heterodimer binds broadly neutralizing antibodies, remains elusive. We present the cryo-electron microscopy (cryoEM) structure of the membrane-extracted full-length E1E2 heterodimer in complex with broadly neutralizing antibodies (bNAbs) AR4A, AT12009 and IGH505 at ~3.5 Å resolution. We resolve the long sought-after interface between the E1 and E2 ectodomains and reveal how it is stabilized by hydrophobic interactions and glycans. This structure deepens our understanding of the HCV fusion glycoprotein and delivers a blueprint for the rational design of novel vaccine immunogens and anti-viral drugs.

scholarly journals Structural flexibility at a major conserved antibody target on hepatitis C virus E2 antigen

2016 ◽  
Vol 113 (45) ◽  
pp. 12768-12773 ◽  
Author(s):  
Leopold Kong ◽  
David E. Lee ◽  
Rameshwar U. Kadam ◽  
Tong Liu ◽  
Erick Giang ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Vaccine Design ◽  
Neutralizing Antibody ◽  
Md Simulations ◽  
Receptor Binding Site ◽  
Structural Investigations ◽  
Thermophilic Organisms

Hepatitis C virus (HCV) is a major cause of liver disease, affecting over 2% of the world’s population. The HCV envelope glycoproteins E1 and E2 mediate viral entry, with E2 being the main target of neutralizing antibody responses. Structural investigations of E2 have produced templates for vaccine design, including the conserved CD81 receptor-binding site (CD81bs) that is a key target of broadly neutralizing antibodies (bNAbs). Unfortunately, immunization with recombinant E2 and E1E2 rarely elicits sufficient levels of bNAbs for protection. To understand the challenges for eliciting bNAb responses against the CD81bs, we investigated the E2 CD81bs by electron microscopy (EM), hydrogen–deuterium exchange (HDX), molecular dynamics (MD), and calorimetry. By EM, we observed that HCV1, a bNAb recognizing the N-terminal region of the CD81bs, bound a soluble E2 core construct from multiple angles of approach, suggesting components of the CD81bs are flexible. HDX of multiple E2 constructs consistently indicated the entire CD81bs was flexible relative to the rest of the E2 protein, which was further confirmed by MD simulations. However, E2 has a high melting temperature of 84.8 °C, which is more akin to proteins from thermophilic organisms. Thus, recombinant E2 is a highly stable protein overall, but with an exceptionally flexible CD81bs. Such flexibility may promote induction of nonneutralizing antibodies over bNAbs to E2 CD81bs, underscoring the necessity of rigidifying this antigenic region as a target for rational vaccine design.

scholarly journals Plasma deconvolution identifies broadly neutralizing antibodies associated with hepatitis C virus clearance

2019 ◽  
Vol 129 (11) ◽  
pp. 4786-4796 ◽  
Author(s):  
Valerie J. Kinchen ◽  
Guido Massaccesi ◽  
Andrew I. Flyak ◽  
Madeleine C. Mankowski ◽  
Michelle D. Colbert ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Virus Clearance

scholarly journals Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance

JCI Insight ◽  
2017 ◽  
Vol 2 (9) ◽  
Author(s):  
Justin R. Bailey ◽  
Andrew I. Flyak ◽  
Valerie J. Cohen ◽  
Hui Li ◽  
Lisa N. Wasilewski ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Somatic Mutations ◽  
Broadly Neutralizing Antibodies ◽  
Virus Clearance

scholarly journals Hepatitis C Virus (HCV)-Induced Immunoglobulin Hypermutation Reduces the Affinity and Neutralizing Activities of Antibodies against HCV Envelope Protein

2008 ◽  
Vol 82 (13) ◽  
pp. 6711-6720 ◽  
Author(s):  
Keigo Machida ◽  
Yasuteru Kondo ◽  
Jeffrey Y. Huang ◽  
Yung-Chia Chen ◽  
Kevin T.-H. Cheng ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cells ◽  
Neutralizing Antibodies ◽  
Immune Surveillance ◽  
Neutralizing Antibody ◽  
Viral Receptor ◽  
Complement Dependent Cytotoxicity ◽  
Protective Antibodies ◽  
Hcv Antibody

ABSTRACT Hepatitis C virus (HCV) often causes persistent infection despite the presence of neutralizing antibodies against the virus in the sera of hepatitis C patients. HCV infects both hepatocytes and B cells through the binding of its envelope glycoprotein E2 to CD81, the putative viral receptor. Previously, we have shown that E2-CD81 interaction induces hypermutation of heavy-chain immunoglobulin (V H ) in B cells. We hypothesize that if HCV infects antibody-producing B cells, the resultant hypermutation of VH may lower the affinity and specificity of the HCV-specific antibodies, enabling HCV to escape from immune surveillance. To test this hypothesis, we infected human hybridoma clones producing either neutralizing or non-neutralizing anti-E2 or anti-E1 antibodies with a lymphotropic HCV (SB strain). All of the hybridoma clones, except for a neutralizing antibody-producing hybridoma, could be infected with HCV and support virus replication for at least 8 weeks after infection. The VH sequences in the infected hybridomas had a significantly higher mutation frequency than those in the uninfected hybridomas, with mutations concentrating in complementarity-determining region 3. These mutations lowered the antibody affinity against the targeting protein and also lowered the virus-neutralizing activity of anti-E2 antibodies. Furthermore, antibody-mediated complement-dependent cytotoxicity with the antibodies secreted from the HCV-infected hybridomas was impaired. These results suggest that HCV infection could cause some anti-HCV-antibody-producing hybridoma B cells to make less-protective antibodies.

Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge

2007 ◽  
Vol 14 (1) ◽  
pp. 25-27 ◽  
Author(s):  
Mansun Law ◽  
Toshiaki Maruyama ◽  
Jamie Lewis ◽  
Erick Giang ◽  
Alexander W Tarr ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies

scholarly journals Antibody Response to Hypervariable Region 1 Interferes with Broadly Neutralizing Antibodies to Hepatitis C Virus

2016 ◽  
Vol 90 (6) ◽  
pp. 3112-3122 ◽  
Author(s):  
Zhen-yong Keck ◽  
Christine Girard-Blanc ◽  
Wenyan Wang ◽  
Patrick Lau ◽  
Adam Zuiani ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Persistent Infection ◽  
Neutralizing Antibodies ◽  
Hypervariable Region ◽  
Humoral Response ◽  
Broadly Neutralizing Antibodies ◽  
Alanine Scanning Mutagenesis ◽  
Effect Analysis ◽  
Hypervariable Region 1

ABSTRACTHypervariable region 1 (HVR1) (amino acids [aa] 384 to 410) on the E2 glycoprotein of hepatitis C virus contributes to persistent infection by evolving escape mutations that attenuate binding of inhibitory antibodies and by blocking access of broadly neutralizing antibodies to their epitopes. A third proposed mechanism of immune antagonism is that poorly neutralizing antibodies binding to HVR1 interfere with binding of other superior neutralizing antibodies. Epitope mapping of human monoclonal antibodies (HMAbs) that bind to an adjacent, conserved domain on E2 encompassing aa 412 to 423 revealed two subsets, designated HC33 HMAbs. While both subsets have contact residues within aa 412 to 423, alanine-scanning mutagenesis suggested that one subset, which includes HC33.8, has an additional contact residue within HVR1. To test for interference of anti-HVR1 antibodies with binding of antibodies to aa 412 to 423 and other E2 determinants recognized by broadly neutralizing HMAbs, two murine MAbs against HVR1 (H77.16) and aa 412 to 423 (H77.39) were studied. As expected, H77.39 inhibited the binding of all HC33 HMAbs. Unexpectedly, H77.16 also inhibited the binding of both subsets of HC33 HMAbs. This inhibition also was observed against other broadly neutralizing HMAbs to epitopes outside aa 412 to 423. Combination antibody neutralization studies by the median-effect analysis method with H77.16 and broadly reactive HMAbs revealed antagonism between these antibodies. Structural studies demonstrated conformational flexibility in this antigenic region, which supports the possibility of anti-HVR1 antibodies hindering the binding of broadly neutralizing MAbs. These findings support the hypothesis that anti-HVR1 antibodies can interfere with a protective humoral response against HCV infection.IMPORTANCEHVR1 contributes to persistent infection by evolving mutations that escape from neutralizing antibodies to HVR1 and by shielding broadly neutralizing antibodies from their epitopes. This study provides insight into a new immune antagonism mechanism by which the binding of antibodies to HVR1 blocks the binding and activity of broadly neutralizing antibodies to HCV. Immunization strategies that avoid the induction of HVR1 antibodies should increase the inhibitory activity of broadly neutralizing anti-HCV antibodies elicited by candidate vaccines.

scholarly journals Hepatitis C Virus Entry: An Intriguingly Complex and Highly Regulated Process

2020 ◽  
Vol 21 (6) ◽  
pp. 2091 ◽  
Author(s):  
Che Colpitts ◽  
Pei-Ling Tsai ◽  
Mirjam Zeisel
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Entry ◽  
Chronic Infection ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Virus Entry ◽  
Host Factors ◽  
Entry Inhibitors

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and liver disease worldwide. Its tissue and species tropism are largely defined by the viral entry process that is required for subsequent productive viral infection and establishment of chronic infection. This review provides an overview of the viral and host factors involved in HCV entry into hepatocytes, summarizes our understanding of the molecular mechanisms governing this process and highlights the therapeutic potential of host-targeting entry inhibitors.

scholarly journals Screening and Rational Design of Hepatitis C Virus Entry Inhibitory Peptides Derived from GB Virus A NS5A

2012 ◽  
Vol 87 (3) ◽  
pp. 1649-1657 ◽  
Author(s):  
Xiuying Liu ◽  
Yibing Huang ◽  
Min Cheng ◽  
Ling Pan ◽  
Youhui Si ◽  
...  
Keyword(s):  
Cell Culture ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Entry ◽  
Rational Design ◽  
Antiviral Drug ◽  
Inhibitory Effect ◽  
Content Type ◽  
Peptide Helicity

ABSTRACTChronic infection by hepatitis C virus (HCV) is a cause of the global burden of liver diseases. HCV entry into hepatocytes is a complicated and multistep process that represents a promising target for antiviral intervention. The recently reported amphipathic α-helical virucidal peptide (C5A) from the HCV NS5A protein suggests a new category of antiviral drug candidates. In this study, to identify C5A-like HCV inhibitors, synthetic peptides derived from the C5A-corresponding NS5 protein region of selectedFlaviviridaeviruses were evaluated for their anti-HCV activities. A peptide from GB virus A (GBV-A), but not other flaviviruses, demonstrated an inhibitory effect on HCV infection. Through a series of sequence optimizations and modifications of the peptide helicity and hydrophobicity, we obtained a peptide designated GBVA10-9 with highly potent anti-HCV activity. GBVA10-9 suppressed infection with both cell culture-derived and pseudotyped HCVin vitro, and the 50% cell culture inhibitory concentration ranged from 20 nM to 160 nM, depending on the genotypic origin of the envelope proteins. GBVA10-9 had no detectable effects on either HCV attachment to Huh7.5.1 cells or viral RNA replication. No virucidal activity was found with GBVA10-9, suggesting an action mechanism distinct from that of C5A. The inhibitory effect of GBVA10-9 appeared to occur at the postbinding step during viral entry. Taken together, the results with GBVA10-9 demonstrated a potent activity for blocking HCV entry that might be used in combination with other antivirals directly targeting virus-encoded enzymes. Furthermore, GBVA10-9 also provides a novel tool to dissect the detailed mechanisms of HCV entry.

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