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

Kinchen, Valerie J.; Massaccesi, Guido; Flyak, Andrew I.; Mankowski, Madeleine C.; Colbert, Michelle D.; Osburn, William O.; Ray, Stuart C.; Cox, Andrea L.; Crowe, James E.; Bailey, Justin R.

doi:10.1172/jci130720

Cited by 38 publications

(59 citation statements)

References 52 publications

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“…In this cohort, plasma samples with bNAb activity were enriched for multi-epitope responses, particularly directed towards AR2, AR3, AR4 and domain D. Interestingly, these combinations were recently shown by 2 independent reports to have synergistic activity in vitro, 11,32 which was superior to individual mAb activities. This supports a recent paper by Kinchen and colleagues, 33 who reported that the induction of AR3 or domain D targeting bNAbs may be important in developing an effective NAb response in combination with AR4-targeting bNAbs. This concordance of findings provides strong evidence for the importance of these epitopes in bNAb responses.…”

Section: Discussionsupporting

confidence: 90%

“…Indeed, failure to account for B cell immunodominance has been suggested to have contributed to the failure of HIV vaccine candidates, as nonneutralising antibodies were induced at the expense of bNAbs. 36 The data reported here and by Kinchen et al 33 similarly suggest that epitopes for vaccine candidates need to be carefully selected, as direction of the natural immune response towards non-neutralising domains was associated with reduced NAb breadth. Subjects with high domain A EMS had significantly more narrow NAb responses compared to those with low domain A scores.…”

Section: Discussionsupporting

confidence: 52%

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B cell immunodominance in primary hepatitis C virus infection

Brasher

Eltahla

Underwood

et al. 2020

Journal of Hepatology

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B cell immunodominance in primary hepatitis C virus infectionGraphical abstract Immunodominance of anti-HCV E1E2 antibodies measured in 168 patientsHighlights Neutralising antibodies will likely form a key component of an HCV vaccine.We characterise the immunodominance of neutralising and non-neutralising epitopes in primary HCV infection.We identify that virus genotype might influence the epitopes targeted.We also identify that certain epitope target combinations are associated with greater breadth.Background & Aims: Neutralising antibodies (NAbs) play a key role in clearance of HCV. NAbs have been isolated and mapped to several domains on the HCV envelope proteins. However, the immunodominance of these epitopes in HCV infection remains unknown, hindering efforts to elicit optimal epitope-specific responses. Furthermore, it remains unclear which epitopespecific responses are associated with broad NAb (bNAb) activity in primary HCV infection. The aim of this study was to define B cell immunodominance in primary HCV, and its implications on neutralisation breadth and clearance. Methods: Using samples from 168 patients with primary HCV infection, the antibody responses targeted 2 immunodominant domains, termed domains B and C. Genotype 1 and 3 infections were associated with responses targeted towards different bNAb domains.Results: No epitopes were uniquely targeted by clearers compared to those who developed chronic infection. Samples with bNAb activity were enriched for multi-specific responses directed towards the epitopes antigenic region 3, antigenic region 4, and domain D, and did not target non-neutralising domains.Conclusions: This study outlines for the first time a clear NAb immunodominance profile in primary HCV infection, and indicates that it is influenced by the infecting virus. It also highlights the need for a vaccination strategy to induce multi-specific responses that do not target non-neutralising domains. Lay summary: Neutralising antibodies will likely form a key component of a protective hepatitis C virus vaccine. In this work we characterise the predominant neutralising and nonneutralising antibody (epitope) targets in acute hepatitis C virus infection. We have defined the natural hierarchy of epitope immunodominance, and demonstrated that viral genotype can impact on this hierarchy. Our findings highlight key epitopes that are associated with broadly neutralising antibodies, and the deleterious impact of mounting a response towards some of these domains on neutralising breadth. These findings should guide future efforts to design immunogens aimed at generating neutralising antibodies with a vaccine candidate.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 52%

B cell immunodominance in primary hepatitis C virus infection

Brasher

Eltahla

Underwood

et al. 2020

Journal of Hepatology

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“…To achieve this, HCV must resist the E1E2-specific nAbs that arise in most individuals. Failure of HCV to evade and/or escape nAbs has been linked with viral clearance and understanding the molecular mechanisms of HCV antibody resistance is likely to inform ongoing HCV vaccine development (Keck et al, 2018;Kinchen et al, 2018Kinchen et al, , 2019.…”

Section: Resultsmentioning

confidence: 99%

An Entropic Safety Catch Controls Hepatitis C Virus Entry and Antibody Resistance

Stejskal

Kalemera

Palor

et al. 2020

Preprint

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E1 and E2 (E1E2), the entry proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Crucially, to allow entry, this mechanism is turned off by host receptor interactions at the cell surface. Thus, HVR-1 is akin to a safety catch on E1E2 activity. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies.

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“…Early appearance of serum nAbs is associated with spontaneous clearance of acute HCV infection and reinfection in humans (8,9). In contrast, subjects with delayed nAb responses often develop persistent infection (9,10).…”

Section: Introductionmentioning

confidence: 99%