Broadly neutralizing antibodies abrogate established hepatitis C virus infection

Jong, Ype P. de; Dorner, Marcus; Mommersteeg, Michiel C.; Xiao, Jing; Balazs, Alejandro B.; Robbins, Justin B.; Winer, Benjamin Y.; Gerges, Sherif; Vega, Kevin; Labitt, Rachael N.; Donovan, Bridget M.; Giang, Erick; Krishnan, Anuradha; Chiriboga, Luis; Charlton, Michael; Burton, Dennis R.; Baltimore, David; Law, Mansun; Rice, Charles M.; Ploß, Alexander

doi:10.1126/scitranslmed.3009512

Cited by 205 publications

(221 citation statements)

References 55 publications

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“…As a comparison, HSA was measured in plasma or sera from three healthy individuals (Donors 1-3). To note, HSA levels in engrafted mice are in accordance with a recently published study on humanized liver in NOD FRG mice (65). E, correlation between HSA and the repopulation index that represents the percentage of human FAH-positive cells in liver sections from PHH-engrafted FRG mice.…”

Section: Frg Mice With Highly Reconstituted Human Liver Allow Productsupporting

confidence: 63%

Functional and Biochemical Characterization of Hepatitis C Virus (HCV) Particles Produced in a Humanized Liver Mouse Model

Calattini¹,

Fusil²,

Mancip³

et al. 2015

Journal of Biological Chemistry

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Background:We compared viral subpopulations derived from humanized liver mouse model versus cell culture. Results:In vivo and in vitro produced particles show different biophysical properties and receptor usage. Conclusion:In vivo models allow functional investigations on how lipid metabolism and hepatic environment influence HCV entry. Significance: HCV produced from humanized liver mice may better reflect the characteristics of virus from HCV-infected patients.

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Section: Frg Mice With Highly Reconstituted Human Liver Allow Productsupporting

confidence: 63%

Functional and Biochemical Characterization of Hepatitis C Virus (HCV) Particles Produced in a Humanized Liver Mouse Model

Calattini¹,

Fusil²,

Mancip³

et al. 2015

Journal of Biological Chemistry

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“…More recently, it has been proposed that the development of a profile consisting of antibodies capable of neutralizing diverse HCV strains (a broadly neutralizing antibody [bNAb]profile) predicts the clearance of acute infection in a cohort infected with genotype 1a (gt1a) HCV (12). Further studies have suggested that bNAbs may be able to control the levels of virus and contribute to clearance even after infection has become established (13). In one case in which a chronically infected patient spontaneously cleared HCV, a bNAb response was initially generated, and subsequently, T cell activity was restored and the infection was resolved (5).…”

mentioning

confidence: 99%

Broad Anti-Hepatitis C Virus (HCV) Antibody Responses Are Associated with Improved Clinical Disease Parameters in Chronic HCV Infection

Swann

Cowton

Robinson

et al. 2016

J Virol

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During hepatitis C virus (HCV) infection, broadly neutralizing antibody (bNAb) responses targeting E1E2 envelope glycopro-teins are generated in many individuals. It is unclear if these antibodies play a protective or a pathogenic role during chronic infection. In this study, we investigated whether bNAb responses in individuals with chronic infection were associated with differences in clinical presentation. Patient-derived purified serum IgG was used to assess the breadth of HCV E1E2 binding and the neutralization activity of HCV pseudoparticles. The binding and neutralization activity results for two panels bearing viral envelope proteins representing either an intergenotype or an intragenotype 1 group were compared. We found that the HCV load was negatively associated with strong cross-genotypic E1E2 binding (P ‫؍‬ 0.03). Overall, we observed only a modest correlation between total E1E2 binding and neutralization ability. The breadth of intergenotype neutralization did not correlate with any clinical parameters; however, analysis of individuals with genotype 1 (gt1) HCV infection (n ‫؍‬ 20), using an intragenotype pseudoparticle panel, found a strong association between neutralization breadth and reduced liver fibrosis (P ‫؍‬ 0.006). A broad bNAb response in our cohort with chronic infection was associated with a single nucleotide polymorphism (SNP) in the HLA-DQB1 gene (P ‫؍‬ 0.038), as previously reported in a cohort with acute disease. Furthermore, the bNAbs in these individuals targeted more than one region of E2-neutralizing epitopes, as assessed through cross-competition of patient bNAbs with well-characterized E2 antibodies. We conclude that the bNAb responses in patients with chronic gt1 infection are associated with lower rates of fibrosis and host genetics may play a role in the ability to raise such responses. IMPORTANCEGlobally, there are 130 million to 150 million people with chronic HCV infection. Typically, the disease is progressive and is a major cause of severe liver cirrhosis and hepatocellular carcinoma. While it is known that neutralizing antibodies have a role in spontaneous clearance during acute infection, little is known about their role in chronic infection. In the present work, we investigated the antibody response in a cohort of chronically infected individuals and found that a broadly neutralizing antibody response is protective and is associated with reduced levels of liver fibrosis and cirrhosis. We also found an association between SNPs in class II HLA genes and the presence of a broadly neutralizing response, indicating that antigen presentation may be important for the production of HCV-neutralizing antibodies. H epatitis C virus (HCV) is a significant cause of liver morbidity and mortality worldwide (1). In the majority (75%) of those infected, the infection proceeds to a chronic infection (2). Symptomatic acute HCV infection is rare; therefore, HCV has the potential to spread undetected among those at risk. In countries with a high prevalence, a poor health care i...

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“…When CD81 and OCLN are overexpressed through adenoviral delivery (21) or transgenically (22), HCV can enter mouse hepatocytes in vivo. While such genetically humanized mice have proven to be useful to study HCV entry and to test approaches focusing on blocking HCV entry (21,(23)(24)(25), a shortcoming is the unphysiologically high expression level achieved by these heterologous expression approaches. Also, neither CD81 nor OCLN is uniquely expressed in the liver; rather, CD81 and OCLN are expressed on all nucleated cells and all tight junctions, respectively.…”

mentioning

confidence: 99%

Mice Expressing Minimally Humanized CD81 and Occludin Genes Support Hepatitis C Virus Uptake In Vivo

Ding

Schaewen

Hrebikova

et al. 2017

J Virol

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Hepatitis C virus (HCV) causes chronic infections in at least 150 million individuals worldwide. HCV has a narrow host range and robustly infects only humans and chimpanzees. The underlying mechanisms for this narrow host range are incompletely understood. At the level of entry, differences in the amino acid sequences between the human and mouse orthologues of two essential host factors, the tetraspanin CD81 and the tight junction protein occludin (OCLN), explain, at least in part, HCV's limited ability to enter mouse hepatocytes. We have previously shown that adenoviral or transgenic overexpression of human CD81 and OCLN facilitates HCV uptake into mouse hepatocytes in vitro and in vivo. In efforts to refine these models, we constructed knock-in mice in which the second extracellular loops of CD81 and OCLN were replaced with the respective human sequences, which contain the determinants that are critical for HCV uptake. We demonstrate that the humanized CD81 and OCLN were expressed at physiological levels in a tissue-appropriate fashion. Mice bearing the humanized alleles formed normal tight junctions and did not exhibit any immunologic abnormalities, indicating that interactions with their physiological ligands were intact. HCV entry factor knock-in mice take up HCV with an efficiency similar to that in mice expressing HCV entry factors transgenically or adenovirally, demonstrating the utility of this model for studying HCV infection in vivo.IMPORTANCE At least 150 million individuals are chronically infected with hepatitis C virus (HCV). Chronic hepatitis C can result in progressive liver disease and liver cancer. New antiviral treatments can cure HCV in the majority of patients, but a vaccine remains elusive. To gain a better understanding of the processes culminating in liver failure and cancer and to prioritize vaccine candidates more efficiently, smallanimal models are needed. Here, we describe the characterization of a new mouse model in which the parts of two host factors that are essential for HCV uptake, CD81 and occludin (OCLN), which differ between mice and humans, were humanized. We demonstrate that such minimally humanized mice develop normally, express the modified genes at physiological levels, and support HCV uptake. This model is of considerable utility for studying viral entry in the three-dimensional context of the liver and to test approaches aimed at preventing HCV entry.KEYWORDS animal models, hepatitis C virus, viral entry, viral hepatitis H epatitis C virus (HCV) is a positive-sense, single-stranded RNA virus belonging to the Flaviviridae family, genus Hepacivirus (1). HCV progresses to persistent infection in 70 to 80% of those individuals who become acutely infected (2). Chronic carriers are at risk of developing fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) if they remain untreated. Over a few years, very potent directly acting antivirals (DAAs) which can cure

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Broadly neutralizing antibodies abrogate established hepatitis C virus infection

Cited by 205 publications

References 55 publications

Functional and Biochemical Characterization of Hepatitis C Virus (HCV) Particles Produced in a Humanized Liver Mouse Model

Functional and Biochemical Characterization of Hepatitis C Virus (HCV) Particles Produced in a Humanized Liver Mouse Model

Broad Anti-Hepatitis C Virus (HCV) Antibody Responses Are Associated with Improved Clinical Disease Parameters in Chronic HCV Infection

Mice Expressing Minimally Humanized CD81 and Occludin Genes Support Hepatitis C Virus Uptake In Vivo

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