Global and local envelope protein dynamics of hepatitis C virus determine broad antibody sensitivity

Broad antibody sensitivity differences of hepatitis C virus (HCV) isolates and their ability to persist in the presence of neutralizing antibodies (NAbs) remain poorly understood. Here, we show that polymorphisms within glycoprotein E2, including hypervariable region 1 (HVR1) and antigenic site 412...

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Published inScience advances Vol. 6; no. 35; p. eabb5938
Main Authors Augestad, Elias H, Castelli, Matteo, Clementi, Nicola, Ströh, Luisa J, Krey, Thomas, Burioni, Roberto, Mancini, Nicasio, Bukh, Jens, Prentoe, Jannick
Format Journal Article
LanguageEnglish
Published United States American Association for the Advancement of Science 01.08.2020
Subjects
Antibodies, Neutralizing
Hepacivirus - genetics
Hepatitis C
Hepatitis C Antibodies
Humans
Immunology
SciAdv r-articles
Viral Envelope Proteins - metabolism
Virology
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Abstract Broad antibody sensitivity differences of hepatitis C virus (HCV) isolates and their ability to persist in the presence of neutralizing antibodies (NAbs) remain poorly understood. Here, we show that polymorphisms within glycoprotein E2, including hypervariable region 1 (HVR1) and antigenic site 412 (AS412), broadly affect NAb sensitivity by shifting global envelope protein conformation dynamics between theoretical "closed," neutralization-resistant and "open," neutralization-sensitive states. The conformational space of AS412 was skewed toward β-hairpin-like conformations in closed states, which also depended on HVR1, assigning function to these enigmatic E2 regions. Scavenger receptor class B, type I entry dependency of HCV was associated with NAb resistance and correlated perfectly with decreased virus propensity to interact with HCV co-receptor CD81, indicating that decreased NAb sensitivity resulted in a more complex entry pathway. This link between global E1/E2 states and functionally distinct AS412 conformations has important implications for targeting AS412 in rational HCV vaccine designs.
AbstractList New insights into hepatitis C virus evasion from neutralizing antibodies have important implications for vaccine development. Broad antibody sensitivity differences of hepatitis C virus (HCV) isolates and their ability to persist in the presence of neutralizing antibodies (NAbs) remain poorly understood. Here, we show that polymorphisms within glycoprotein E2, including hypervariable region 1 (HVR1) and antigenic site 412 (AS412), broadly affect NAb sensitivity by shifting global envelope protein conformation dynamics between theoretical “closed,” neutralization-resistant and “open,” neutralization-sensitive states. The conformational space of AS412 was skewed toward β-hairpin–like conformations in closed states, which also depended on HVR1, assigning function to these enigmatic E2 regions. Scavenger receptor class B, type I entry dependency of HCV was associated with NAb resistance and correlated perfectly with decreased virus propensity to interact with HCV co-receptor CD81, indicating that decreased NAb sensitivity resulted in a more complex entry pathway. This link between global E1/E2 states and functionally distinct AS412 conformations has important implications for targeting AS412 in rational HCV vaccine designs.
Broad antibody sensitivity differences of hepatitis C virus (HCV) isolates and their ability to persist in the presence of neutralizing antibodies (NAbs) remain poorly understood. Here, we show that polymorphisms within glycoprotein E2, including hypervariable region 1 (HVR1) and antigenic site 412 (AS412), broadly affect NAb sensitivity by shifting global envelope protein conformation dynamics between theoretical "closed," neutralization-resistant and "open," neutralization-sensitive states. The conformational space of AS412 was skewed toward β-hairpin-like conformations in closed states, which also depended on HVR1, assigning function to these enigmatic E2 regions. Scavenger receptor class B, type I entry dependency of HCV was associated with NAb resistance and correlated perfectly with decreased virus propensity to interact with HCV co-receptor CD81, indicating that decreased NAb sensitivity resulted in a more complex entry pathway. This link between global E1/E2 states and functionally distinct AS412 conformations has important implications for targeting AS412 in rational HCV vaccine designs.
Author Prentoe, Jannick
Ströh, Luisa J
Bukh, Jens
Krey, Thomas
Castelli, Matteo
Clementi, Nicola
Mancini, Nicasio
Augestad, Elias H
Burioni, Roberto
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Snippet Broad antibody sensitivity differences of hepatitis C virus (HCV) isolates and their ability to persist in the presence of neutralizing antibodies (NAbs)...
New insights into hepatitis C virus evasion from neutralizing antibodies have important implications for vaccine development. Broad antibody sensitivity...
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SubjectTerms Antibodies, Neutralizing
Hepacivirus - genetics
Hepatitis C
Hepatitis C Antibodies
Humans
Immunology
SciAdv r-articles
Viral Envelope Proteins - metabolism
Virology
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Title Global and local envelope protein dynamics of hepatitis C virus determine broad antibody sensitivity
URI https://www.ncbi.nlm.nih.gov/pubmed/32923643
https://search.proquest.com/docview/2442596190
https://pubmed.ncbi.nlm.nih.gov/PMC7449684
Volume 6
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