Sites of vulnerability in HCV E1E2 identified by comprehensive functional screening

Pfaff-Kilgore, Jennifer M.; Davidson, Edgar; Kadash-Edmondson, Kathryn E.; Hernandez, Mayda; Rosenberg, Erin; Chambers, Ross; Castelli, Matteo; Clementi, Nicola; Mancini, Nicasio; Bailey, Justin R.; Crowe, James E.; Law, Mansun; Doranz, Benjamin J.

doi:10.1016/j.celrep.2022.110859

Cited by 17 publications

(20 citation statements)

References 112 publications

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“…S6). These data are consistent with and provide a structural basis for the results of a recent alanine scanning mutagenesis study on E1E2 pseudovirus (45), which also reported that amino acids R657, D658, L692, and Q700 in E2 and Y201, T204, N205, and D206 in E1 are crucial for infectivity (fig. S5, B to F) (D, aspartate).…”

Section: The E1e2 Interfacesupporting

confidence: 89%

“…Similarly, structures of prefusion HIV-1 Env and respiratory syncytial virus (RSV) F were solved using conformational prefusion-specific antibodies ( 54 , 57 ). The viral entry pathway after CD81 binding likely involves a multistep process in which the interface of the E1E2 glycoprotein complex is destabilized and opens up upon low pH and/or receptor binding, triggering downstream conformational changes that expose the fusion peptide on E1 and induce viral fusion ( 24 , 45 ). Neutralizing antibodies can therefore either block CD81 binding by direct competition—for example, AT1209—or, if bound outside the receptor binding site, can impede entry by blocking conformational changes required for fusion, for example, AR4A and IGH505.…”

Section: Discussionmentioning

confidence: 99%

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Structure of the hepatitis C virus E1E2 glycoprotein complex

Peña

Sliepen

Eshun-Wilson

et al. 2022

Science

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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 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, remain elusive. Here, we present the cryo–electron microscopy structure of the membrane-extracted full-length E1E2 heterodimer in complex with three broadly neutralizing antibodies—AR4A, AT1209, and IGH505—at ~3.5-angstrom resolution. We resolve the interface between the E1 and E2 ectodomains and deliver a blueprint for the rational design of vaccine immunogens and antiviral drugs.

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Section: The E1e2 Interfacesupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Structure of the hepatitis C virus E1E2 glycoprotein complex

Peña

Sliepen

Eshun-Wilson

et al. 2022

Science

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“…A recent experimental study has shown that E1E2 is a fragile protein complex wherein even a single alanine mutation at 92% of positions abrogates replicative capacity of the virus [43]. Therefore, our finding that 70% of the top 300 pairs of mutations (ranked by absolute values of J ij ) between E1 and E2 are compensatory suggests that these interactions may play a significant role in mediating viral fitness.…”

Section: Discussionmentioning

confidence: 57%

“…S2). A recent study reported E1E2 as a highly fragile complex, with 92% of alanine mutations introduced independently at each residue severely impacting virus fitness [43]. The strong compensatory interactions identified in our analysis indicate a potential mechanism by which E1 and E2, the most variable HCV proteins, may make multiple mutations while maintaining viral fitness.…”

Section: Majority Of Strong E1e2 Inter-protein Interactions Are Compe...mentioning

confidence: 53%

“…We compiled a total of 156 in-vitro infectivity measurements for E1E2 from 16 studies [13], [29]- [43]. We found that the JM provided a stronger negative Spearman correlation (r = −0.70; see Methods for details) between the predicted sequence energies (inversely related to prevalence) and experimental fitness values (Fig.…”

Section: B E1e2 Inter-protein Interactions Are Important In Mediating...mentioning

confidence: 99%

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HCV E1 influences the fitness landscape of E2 and may enhance escape from E2-specific antibodies

Zhang

Bull

Quadeer

et al. 2023

Preprint

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The Hepatitis C virus (HCV) envelope glycoprotein E1 forms a noncovalent heterodimer with E2, the main target of neutralizing antibodies. How E1-E2 interactions influence viral fitness and contribute to resistance to E2-specific antibodies remains largely unknown. We investigate this problem using a combination of fitness landscape and evolutionary modelling. Our analysis indicates that E1 and E2 proteins collectively mediate viral fitness, and suggests that fitness-compensating E1 mutations may accelerate escape from E2-targeting antibodies. Our analysis also identifies a set of E2-specific human monoclonal antibodies that are predicted to be especially resilient to escape via genetic variation in both E1 and E2, providing directions for robust HCV vaccine development.

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