A5017501489- Hepatitis C virus research
- Monoclonal and Polyclonal Antibodies Research
- Hepatitis B Virus Studies
- HIV Research and Treatment
- Viral gastroenteritis research and epidemiology
- Animal Virus Infections Studies
- Virus-based gene therapy research
- Liver Disease Diagnosis and Treatment
- Influenza Virus Research Studies
- Systemic Lupus Erythematosus Research
- Glycosylation and Glycoproteins Research
Copenhagen University Hospital
2019-2024
University of Copenhagen
2015-2024
Hvidovre Hospital
2015-2022
Universidad Nacional Autónoma de México
2011-2012
There are 3‐4 million new hepatitis C virus (HCV) infections yearly. The extensive intergenotypic sequence diversity of envelope proteins E1 and E2 HCV shielding important epitopes by hypervariable region 1 (HVR1) believed to be major hindrances developing universally protective vaccines. Using cultured viruses expressing the E1/E2 complex isolates H77 (genotype 1a), J6 (2a), or S52 (3a), with without HVR1, we tested HVR1‐mediated neutralization occlusion in vitro against a panel 12...
Cumulative evidence supports a role for neutralizing antibodies contributing to spontaneous viral clearance during acute hepatitis C virus (HCV) infection. Information on the timing and specificity of B cell response associated with is crucial inform vaccine design. From an individual who cleared three sequential HCV infections genotypes 1b, 1a 3a strains, respectively, we employed peripheral cells isolate characterize human monoclonal (HMAbs) after genotype 1 infections. The majority...
Significance Hepatitis C virus (HCV) is a pervasive human pathogen for which vaccine urgently needed. Vaccine development relies on inducing neutralizing antibodies (NAbs), but HCV employs complex mechanisms to evade neutralization that remain incompletely understood. Here, we discover unique interplay between two separate molecular features of envelope protein E2, the hypervariable region 1 and N-linked glycans, protect from NAbs. Furthermore, find they share mechanism in broadly modulate...
<h3>Objective</h3> HCV is a major cause of chronic liver disease worldwide, but the role neutralising antibodies (nAbs) in its natural history remains poorly defined. We analysed vivo hypervariable region 1 (HVR1) for virion properties, including nAb susceptibility. <h3>Design</h3> Analysis from human chimeric mice infected with cell-culture-derived prototype genotype 2a recombinant J6/JFH1 or HVR1-deleted variant J6/JFH1<sub>ΔHVR1</sub> identified adaptive mutations, which were by reverse...
An alternate conformation is found for the major antibody target on hepatitis C virus to aid in rational vaccine design.
HCV infection continues to be a major global health burden despite effective antiviral treatments. The urgent need for protective vaccine is hindered by the scarcity of suitable HCV-permissive animal models tractable in vaccination and challenge studies. Currently, only antibody neutralization studies infectious cell culture systems or protection passive immunization human liver chimeric mice offer possibility evaluate effect vaccine-induced antibodies. However, differences between...
Hepatitis C virus (HCV) is a leading cause of liver-related mortality, and limited treatment accessibility makes vaccine development high priority. The vaccine-relevant cross-genotype-reactive antibody AR3A has shown potency, but the ability to rapidly escape by mutating epitope (barrier resistance) remains unexplored. Here, we succeeded in inducing only low-level resistance, indicating higher barrier resistance than what have previously reported for AR5A. Furthermore, identify substitutions...
Hepatitis C virus (HCV) is a major cause of end-stage liver diseases. With 3–4 million new HCV infections yearly, vaccine urgently needed. A better understanding escape from neutralizing antibodies and their corresponding epitopes are important for this effort. However, viral isolates with high antibody resistance, or moderate potency, it remains challenging to induce mutations in vitro. Here, as proof-of-concept, we used antibody-sensitive HVR1-deleted (ΔHVR1) viruses generate mutants human...
Global control of hepatitis C virus (HCV) depends on development a prophylactic vaccine. We studied escape for cross-genotype-reactive neutralizing antibody AR4A, providing valuable information HCV vaccine design. cultured core-NS2 recombinants H77 (genotype 1a)/JFH1 or the highly antibody-susceptible hypervariable region 1 (HVR1)-deleted variants H77/JFH1∆HVR1 and J6(genotype 2a)/JFH1∆HVR1 in Huh7.5 cells with AR4A. Long-term AR4A exposure H77/JFH1 did not yield resistance. However,...
Background and Aims: Chronic hepatitis C virus (HCV) infection afflicts around 50 million people globally, causing ~250,000 deaths yearly. An effective vaccine needs to overcome high viral diversity HCV’s ability evade neutralizing antibodies (NAbs). Rapid antigenic drift in the N-terminal motif of envelope protein E2, named hypervariable region 1 (HVR1), is critically involved NAb evasion via an incompletely understood mechanism involving entry factors. The canonical length HVR1 27 amino...
Background and Aims: HCV evasion of neutralizing antibodies (nAb) results in viral persistence poses challenges to the development an urgently needed vaccine. N‐linked glycosylation envelope proteins is a key mechanism for such evasion. To facilitate rational vaccine design, we aimed identify determinants protection conserved epitopes. Approach Results: Using reverse evolutionary approach, passaged genotype 1a, 1b, 2a, 3a, 4a with (E1 E2) derived from chronically infected patients without...
Abstract Development of B-cell-based hepatitis C virus (HCV) vaccines that induce broadly neutralizing antibodies (bNAbs) is hindered by extensive sequence diversity and low immunogenicity envelope glycoprotein vaccine candidates, most notably soluble E2 (sE2). To overcome this, we employed two-component approaches using self-assembling virus-like particles (cVLPs; component 1), displaying monomeric or oligomeric forms HCV sE2 (sE2 mono oligo ; 2). Immunization studies were performed in...
Abstract Worldwide, 58 million individuals suffer from chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer. The HCV envelope proteins, E1 and E2, form heterodimer, which is the target for neutralizing antibodies. Despite high-resolution structural models partial heterodimer elements, landscape higher-order E1/E2 oligomers remains unexplored. We determined ~3.5 Å cryo-electron microscopy structure membrane-extracted in homodimeric arrangement. This includes detailed...
Hepatitis C virus (HCV) genotype 4 is highly prevalent in the Middle East and parts of Africa. Subtype 4d has recently spread among high-risk groups Europe. However, infectious culture systems are not available, hampering studies drugs, as well neutralizing antibodies relevant for HCV vaccine development. We determined consensus sequence from a chronic hepatitis patient by next-generation sequencing, generated full-length clone thereof (pDH13), demonstrated that pDH13 RNA-transcripts were...
Yearly, about 1.5 million people become chronically infected with hepatitis C virus (HCV) and for the 71 chronic HCV infection 400,000 die from related morbidities, including liver cirrhosis cancer. Effective treatments exist, but challenges cost-of-treatment wide-spread undiagnosed infection, necessitates development of vaccines. Vaccines should induce neutralizing antibodies (NAbs) against envelope (E) transmembrane glycoprotein 2, E2, which partly depends on its interaction partner, E1,...
first_page settings Order Article Reprints Font Type: Arial Georgia Verdana Size: Aa Line Spacing: Column Width: Background: Open AccessExtended Abstract Identification of Novel Determinants Neutralization Epitope Shielding for Hepatitis C Virus in Vitro † by Garazi Peña Alzua 1,2,‡, Anne Finne Pihl Anna Falden Offersgaard 1,2, Rodrigo Velázquez-Moctezuma Elias Honeroed Augestad Ulrik Fahnøe Christian Kjaerulff Mathiesen Mansun Law 3, Jannick Prentoe Jens Bukh 1,2 and Judith Margarete...