HCV Broadly Neutralizing Antibodies Use a CDRH3 Disulfide Motif to Recognize an E2 Glycoprotein Site that Can Be Targeted for Vaccine Design

Flyak, Andrew I.; Ruiz, Stormy; Colbert, Michelle D.; Luong, Tiffany; Crowe, James E.; Bailey, Justin R.; Björkman, Pamela J.

doi:10.1016/j.chom.2018.10.009

Cited by 105 publications

(220 citation statements)

References 58 publications

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“…Binding of the E2 glycoprotein of hepatitis C virus (HCV) to the large extracellular loop of CD81 is a defining event in the entry of HCV [1] and is targeted by multiple broadly neutralising antibodies; thus placing this molecular interaction at the forefront of current HCV vaccine development [2,3]. Whilst the importance of CD81 in HCV entry is well established, the precise details of E2-CD81 interaction have yet to be defined and the molecular determinants of CD81 receptor activity are only partially understood [4].…”

Section: Introductionmentioning

confidence: 99%

Cholesterol sensing by CD81 is important for hepatitis C virus entry

Palor

Stejskal

Mandal

et al. 2019

Preprint

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a These authors contributed equally to this work CD81 is a multifunctional protein that plays a central role in both physiological and pathological processes. Recent structural analysis of CD81 indicates that it adopts a compact fold with its large extracellular loop sitting close to the plasma membrane; however, there is evidence that CD81 can undergo a conformational switch where the extracellular loop flips into an extended open conformation. We investigated the relevance of CD81 conformational switching to its function as a receptor for hepatitis C virus (HCV). Structure-led mutagenesis was used to generate CD81 variants with altered conformational switching. Each variant maintained proper protein folding and expression, and retained a basic function: the ability to chaperone CD19 to the cell surface. We then used multiple systems to evaluate HCV receptor activity; in these experiments 'open' CD81 variants exhibited consistently poor receptor function, whereas a 'closed' CD81 displayed enhanced ability to support HCV entry. We sought to corroborate these findings by exploring CD81 structural flexibility using molecular dynamics simulations. These experiments were in excellent agreement with our in vitro work, with 'open' CD81 variants having a propensity to undergo conformational switching. Taken together, we provide evidence for a conformational switch in CD81 that regulates its HCV receptor activity. This work furthers our understanding of the molecular mechanism of HCV entry and is relevant to CD81's other functions in health and disease.

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Section: Introductionmentioning

confidence: 99%

Cholesterol sensing by CD81 is important for hepatitis C virus entry

Palor

Stejskal

Mandal

et al. 2019

Preprint

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“…Finally, the infectivity of genotype 1b is not significantly affected by the presence of any hCD81 variant included in this study. We, therefore, compared the HCV E2 amino acid residues, described to contribute to hCD81 binding [36][37][38][39] for the seven HCV genotypes ( Fig S5a). While all the genotypes consistently display large hydrophobic aromatic amino acids in the four critical hCD81-binding regions, the hCD81 SNV-sensitive genotypes harbour an amino acid variation at position 444 in E2 region 4.…”

Section: Hcd81 Variant-expressing Cells Are Differentially Permissivementioning

confidence: 99%

Single-nucleotide variants in human CD81 influence hepatitis C virus infection of hepatoma cells

Alberione

Moeller

Kirui

et al. 2020

Med Microbiol Immunol

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An estimated number of 71 million people are living with chronic hepatitis C virus (HCV) infection worldwide and 400,000 annual deaths are related to the infection. HCV entry into the hepatocytes is complex and involves several host factors. The tetraspanin human CD81 (hCD81) is one of the four essential entry factors and is composed of one large extracellular loop, one small extracellular loop, four transmembrane domains, one intracellular loop and two intracellular tails. The large extracellular loop interacts with the E2 glycoprotein of HCV. Regions outside the large extracellular loop (backbone) of hCD81 have a critical role in post-binding entry steps and determine susceptibility of hepatocytes to HCV. Here, we investigated the effect of five non-synonymous single-nucleotide variants in the backbone of hCD81 on HCV susceptibility. We generated cell lines that stably express the hCD81 variants and infected the cells using HCV pseudoparticles and cell culture-derived HCV. Our results show that all the tested hCD81 variants support HCV pseudoparticle entry with similar efficiency as wildtype hCD81. In contrast, variants A54V, V211M and M220I are less supportive to cell culture-derived HCV infection. This altered susceptibility is HCV genotype dependent and specifically affected the cell entry step. Our findings identify three hCD81 genetic variants that are impaired in their function as HCV host factors for specific viral genotypes. This study provides additional evidence that genetic host variation contributes to inter-individual differences in HCV infection and outcome.

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“…6,7 Despite the heuristic appeal of the lock and key model, interactions between antibodies and antigens, particularly paratopes with epitopes, are far more complex than the static, inert image a lock and key conveys. Ehrlich had already concluded that that antibody and antigen might fit each other like a key in a lock (a metaphor borrowed from Emil Fischer 5 ).…”

Section: B Cell Toler An Ce In Three Dimens Ionsmentioning

confidence: 99%

“…The idea that the specificity of antibody and hence B cell recognition derives to a considerable extent from the three dimensional interaction of paratope and epitope traces to the lock and key model and that metaphor is still used to describe some antibody-antigen interactions. 6,7 Despite the heuristic appeal of the lock and key model, interactions between antibodies and antigens, particularly paratopes with epitopes, are far more complex than the static, inert image a lock and key conveys. The three dimensional structures of antibodies do appear to fit some antigens, but forces never imagined in the original model govern the rate and extent or association and the permanence of binding.…”

Section: B Cell Toler An Ce In Three Dimens Ionsmentioning

confidence: 99%

The five dimensions of B cell tolerance

Platt

Barbosa

Cascalho

2019

Immunological Reviews

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B cell tolerance has been generally understood to be an acquired property of the immune system that governs antibody specificity in ways that avoid auto-toxicity.As useful as this understanding has proved, it fails to fully explain the existence of auto-reactive specificities in healthy individuals and contribution these may have to health. Mechanisms underlying B cell tolerance are considered to select a clonal repertoire that generates a collection of antibodies that do not bind self, ie tolerance operates more or less in three dimensions that largely spare autologous cells andantigens. Yet, most B lymphocytes in humans and probably in other vertebrates are auto-reactive and absence of these auto-reactive B cells is associated with disease.We suggest that auto-reactivity can be embodied by extending the concept of tolerance by two further dimensions, one of time and circumstance and one that allows healthy cells to actively resist injury. In this novel concept, macromolecular recognition by the B cell receptor leading to deletion, anergy, receptor editing or B cell activation is extended by taking account of the time of development of normal immune responses (4th dimension) and the accommodation (or tolerance) of normal cells to bound antibody, activation of complement, and interaction with inflammatory cells (fifth dimension). We discuss how these dimensions contribute to understanding B cell biology in health or disease. K E Y W O R D S

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HCV Broadly Neutralizing Antibodies Use a CDRH3 Disulfide Motif to Recognize an E2 Glycoprotein Site that Can Be Targeted for Vaccine Design

Cited by 105 publications

References 58 publications

Cholesterol sensing by CD81 is important for hepatitis C virus entry

Cholesterol sensing by CD81 is important for hepatitis C virus entry

Single-nucleotide variants in human CD81 influence hepatitis C virus infection of hepatoma cells

The five dimensions of B cell tolerance

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