The role of neutralizing antibodies in hepatitis C virus infection

Hepatitis C virus (HCV) is a blood-borne virus estimated to infect around 170 million people worldwide and is, therefore, a major disease burden. In some individuals the virus is spontaneously cleared during the acute phase of infection, whilst in others a persistent infection ensues. Of those persistently infected, severe liver diseases such as cirrhosis and primary liver cancer may develop, although many individuals remain asymptomatic. A range of factors shape the course of HCV infection, not least host genetic polymorphisms and host immunity. A number of studies have shown that neutralizing antibodies (nAb) arise during HCV infection, but that these antibodies differ in their breadth and mechanism of neutralization. Recent studies, using both mAbs and polyclonal sera, have provided an insight into neutralizing determinants and the likely protective role of antibodies during infection. This understanding has helped to shape our knowledge of the overall structure of the HCV envelope glycoproteins – the natural target for nAb. Most nAb identified to date target receptor-binding sites within the envelope glycoprotein E2. However, there is some evidence that other viral epitopes may be targets for antibody neutralization, suggesting the need to broaden the search for neutralization epitopes beyond E2. This review provides a comprehensive overview of our current understanding of the role played by nAb in HCV infection and disease outcome and explores the limitations in the study systems currently used. In addition, we briefly discuss the potential therapeutic benefits of nAb and efforts to develop nAb-based therapies.

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Previously Infected Chimpanzees Are Not Consistently Protected against Reinfection or Persistent Infection after Reexposure to the Identical Hepatitis C Virus Strain

Journal of Virology ◽

10.1128/jvi.00142-08 ◽

2008 ◽

Vol 82 (16) ◽

pp. 8183-8195 ◽

Cited By ~ 63

Author(s):

Jens Bukh ◽

Robert Thimme ◽

Jean-Christophe Meunier ◽

Kristina Faulk ◽

Hans Christian Spangenberg ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Persistent Infection ◽

Neutralizing Antibodies ◽

Hcv Infection ◽

Case Scenario ◽

Cell Responses ◽

Genotype 1A ◽

Cellular Immune

ABSTRACT Protective immunity after resolved hepatitis C virus (HCV) infection has been reported. However, the breadth of this immunity has remained controversial, and the role of neutralizing antibodies has not been well-defined. In the present study, two chimpanzees (CH96A008 and CH1494) with resolved monoclonal H77C (genotype 1a) infection were rechallenged with low-dose homologous H77C virus about 12 months after viral clearance; CH96A008 became persistently infected, and CH1494 had transient viremia lasting 2 weeks. CH1494 was subsequently either partially or completely protected following five homologous rechallenges with monoclonal H77C or polyclonal H77 and after six heterologous rechallenges with HC-J4 (genotype 1b) or HC-J6 (genotype 2a) viruses. Subsequently, a final challenge with H77C resulted in persistent HCV infection. In both chimpanzees, serum neutralizing antibodies against retroviral pseudoparticles bearing the H77C envelope proteins were not detected during the initial infection or during rechallenge. However, anamnestic cellular immune responses developed during the initial homologous rechallenge, in particular in CH96A008, which developed a persistent infection. Polyprotein sequences of viruses recovered from CH1494 after the two homologous rechallenges that resulted in transient viremia were identical with the H77C virus. In contrast, the polyprotein sequences of viruses recovered from both chimpanzees after homologous rechallenge resulting in persistent infection had numerous changes. These findings have important implications for our understanding of immunity against HCV; even in the best-case scenario with autologous rechallenge, low-level viral persistence was seen in the presence of primed T-cell responses.

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Hepatitis C Virus Infection and B-Cell Non-Hodgkin’s Lymphoma.

Blood ◽

10.1182/blood.v106.11.4668.4668 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4668-4668

Author(s):

Janet G. Grudeva

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Hcv Infection ◽

Control Group ◽

Cell Infection ◽

Serum Samples ◽

Pathogenetic Role ◽

Significant Difference

Backgroud: An increasing number of bacterial and viral infections have been linked with specific subtypes of lymphoma. Preliminary evidence suggests that hepatitis C virus (HCV) might play a pathogenetic role in autoimmune-related, non-malignant B-cell lymphoproliferation, as well as a subset of B-cell non-Hodgkin, s lymphomas (B-NHL), often with extranodal localization. Design and methods: The study was conducted in the Department of Hematology and consisted 149 (86 male, 63 female) untreated patients with a new diagnosis of B-NHL for 5-years period (2000–2004). HCV infection was investigated by testing for HCV antibodies in serum samples. The controls were 587 patients (without intravenous drug users) in other departments of the same hospital. Results: HCV infection was documented in 13 cases (8,4%) with NHL. The infected patients were not clinically relevant cryoglobulinemic activity, increased rate of autoimmune disorders and extranodal localizations prevalence. There was statistically significant difference between the NHL and control group (p<0,01) and no statistically significant difference between man/women carriers (p>0,05) into the NHL group. Overall, the clinical outcome of HCV-positive NHL does not seem to be different from that of NHL patients without HCV infection. However, the evidence of a significant liver injury may predict a worse prognosis in these cases. Conclusions: Our date suggest that HCV infection may be associated with B-NHL. With regard to the mechanism(s) by which HCV might favor B-cell expansion and malignant transformation, most date support an indirect pathogenetic role of the virus as an exogenous trigger. A direct oncogenetic role of HCV by direct cell infection and deregulation has only been hypothesized on the basis of the lymphotropism of the virus.

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Hepatitis C Virus (HCV) Infection May Elicit Neutralizing Antibodies Targeting Epitopes Conserved in All Viral Genotypes

PLoS ONE ◽

10.1371/journal.pone.0008254 ◽

2009 ◽

Vol 4 (12) ◽

pp. e8254 ◽

Cited By ~ 45

Author(s):

Nicasio Mancini ◽

Roberta A. Diotti ◽

Mario Perotti ◽

Giuseppe Sautto ◽

Nicola Clementi ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Neutralizing Antibodies ◽

Hcv Infection

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Role of Anti-Hepatitis C Virus (HCV) Treatment in HCV-Related, Low-Grade, B-Cell, Non-Hodgkin's Lymphoma: A Multicenter Italian Experience

Journal of Clinical Oncology ◽

10.1200/jco.2005.06.008 ◽

2005 ◽

Vol 23 (3) ◽

pp. 468-473 ◽

Cited By ~ 174

Author(s):

Daniele Vallisa ◽

Patrizia Bernuzzi ◽

Luca Arcaini ◽

Stefano Sacchi ◽

Vittorio Callea ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Antiviral Treatment ◽

Complete Response ◽

Hcv Infection ◽

Low Grade ◽

Hcv Treatment ◽

Hematologic Response

Purpose Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkin's lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated. Patients and Methods Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months. Results Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 ± 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response. Conclusion This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.

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In Vivo Study of the HC-TN Strain of Hepatitis C Virus Recovered from a Patient with Fulminant Hepatitis: RNA Transcripts of a Molecular Clone (pHC-TN) Are Infectious in Chimpanzees but Not in Huh7.5 Cells

Journal of Virology ◽

10.1128/jvi.01774-06 ◽

2007 ◽

Vol 81 (13) ◽

pp. 7208-7219 ◽

Cited By ~ 41

Author(s):

Akito Sakai ◽

Shingo Takikawa ◽

Robert Thimme ◽

Jean-Christophe Meunier ◽

Hans Christian Spangenberg ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Immune Responses ◽

Disease Severity ◽

Neutralizing Antibodies ◽

Viral Evolution ◽

Acute Infection ◽

Hcv Infection ◽

Rna Transcripts

ABSTRACT Both viral and host factors are thought to influence the pathogenesis of hepatitis C virus (HCV) infection. We studied strain HC-TN (genotype 1a), which caused fulminant hepatic failure in a patient and, subsequently, severe hepatitis in a chimpanzee (CH1422), to analyze the relationship between disease severity, host immune response, viral evolution, and outcome. A second chimpanzee (CH1581) was infected from CH1422 plasma, and a third chimpanzee (CH1579) was infected from RNA transcripts of a consensus cDNA of HC-TN (pHC-TN). RNA transcripts of pHC-TN did not replicate in Huh7.5 cells, which were recently found to be susceptible to infection with another fulminant HCV strain (JFH1). The courses of viremia were similar in the three animals. However, CH1581 and CH1579 developed a less severe acute hepatitis than CH1422. CH1579 and CH1422 resolved the infection, whereas CH1581 became persistently infected. CH1579 and CH1581, despite their differing outcomes, both developed significant intrahepatic cellular immune responses, but not antibodies to the envelope glycoproteins or neutralizing antibodies, during the acute infection. We analyzed the polyprotein sequences of virus recovered at five and nine time points from CH1579 and CH1581, respectively, during the first year of follow-up. High mutation rates and high proportions of nonsynonymous mutations suggested immune pressure and positive selection in both animals. Changes were not selected until after the initial decrease in virus titers and after the development of immune responses and hepatitis. Subsequently, however, mutations emerged repeatedly in both animals. Overall, our results indicate that disease severity and outcome of acute HCV infection depend primarily on the host response.

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Neglected but Important Role of Apolipoprotein E Exchange in Hepatitis C Virus Infection

Journal of Virology ◽

10.1128/jvi.01353-16 ◽

2016 ◽

Vol 90 (21) ◽

pp. 9632-9643 ◽

Cited By ~ 30

Author(s):

Zaili Yang ◽

Xiaoning Wang ◽

Xiumei Chi ◽

Fanfan Zhao ◽

Jinxu Guo ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Cell Surface ◽

Apolipoprotein E ◽

Virus Assembly ◽

Hcv Infection ◽

Apoe Level ◽

New Perspective ◽

Apoe Expression

ABSTRACT Hepatitis C virus (HCV) is a major cause of chronic liver disease, infecting approximately 170 million people worldwide. HCV assembly is tightly associated with the lipoprotein pathway. Exchangeable apolipoprotein E (apoE) is incorporated on infectious HCV virions and is important for infectious HCV virion morphogenesis and entry. Moreover, the virion apoE level is positively correlated with its ability to escape E2 antibody neutralization. However, the role of apoE exchange in the HCV life cycle is unclear. In this study, the relationship between apoE expression and cell permissiveness to HCV infection was assessed by infecting apoE knockdown and derived apoE rescue cell lines with HCV. Exchange of apoE between lipoproteins and HCV lipoviral particles (LVPs) was evaluated by immunoprecipitation, infectivity testing, and viral genome quantification. Cell and heparin column binding assays were applied to determine the attachment efficiency of LVPs with different levels of incorporated apoE. The results showed that cell permissiveness for HCV infection was determined by exogenous apoE-associated lipoproteins. Furthermore, apoE exchange did occur between HCV LVPs and lipoproteins, which was important to maintain a high apoE level on LVPs. Lipid-free apoE was capable of enhancing HCV infectivity for apoE knockdown cells but not apoE rescue cells. A higher apoE level on LVPs conferred more efficient LVP attachment to both the cell surface and heparin beads. This study revealed that exogenous apoE-incorporating lipoproteins from uninfected hepatocytes safeguarded the apoE level of LVPs for more efficient attachment during HCV infection. IMPORTANCE In this study, a neglected but important role of apoE exchange in HCV LVP infectivity after virus assembly and release was identified. The data indicated that apoE expression level in uninfected cells is important for high permissiveness to HCV infection. Secreted apoE-associated lipoprotein specifically enhances infection of HCV LVPs. apoE exchange between HCV LVP and lipoproteins is important to maintain an adequate apoE level on LVPs for their efficient attachment to cell surface. These data defined for the first time an extracellular role of exchangeable apoE in HCV infection and suggested that exchangeable apolipoproteins reach a natural equilibrium between HCV LVPs and lipoprotein particles, which provides a new perspective to the understanding of the heterogeneity of HCV LVPs in composition.

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The role of cytotoxic T lymphocytes in hepatitis C virus (HCV) infection

Immunology Letters ◽

10.1016/s0165-2478(97)86201-3 ◽

1997 ◽

Vol 56 ◽

pp. 298

Author(s):

N.B.C. Bovee ◽

M.R. Klein ◽

M. Damen ◽

M. Beld ◽

H.T.M. Cuypers ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Hcv Infection

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Role of N-Linked Glycans in the Functions of Hepatitis C Virus Envelope Proteins Incorporated into Infectious Virions

Journal of Virology ◽

10.1128/jvi.01548-10 ◽

2010 ◽

Vol 84 (22) ◽

pp. 11905-11915 ◽

Cited By ~ 138

Author(s):

François Helle ◽

Gabrielle Vieyres ◽

Laure Elkrief ◽

Costin-Ioan Popescu ◽

Czeslaw Wychowski ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Neutralizing Antibodies ◽

Point Mutations ◽

Envelope Proteins ◽

Envelope Glycoproteins ◽

Virus Envelope ◽

Humoral Immune ◽

A Cell

ABSTRACT Hepatitis C virus (HCV) envelope glycoproteins are highly glycosylated, with generally 4 and 11 N-linked glycans on E1 and E2, respectively. Studies using mutated recombinant HCV envelope glycoproteins incorporated into retroviral pseudoparticles (HCVpp) suggest that some glycans play a role in protein folding, virus entry, and protection against neutralization. The development of a cell culture system producing infectious particles (HCVcc) in hepatoma cells provides an opportunity to characterize the role of these glycans in the context of authentic infectious virions. Here, we used HCVcc in which point mutations were engineered at N-linked glycosylation sites to determine the role of these glycans in the functions of HCV envelope proteins. The mutants were characterized for their effects on virus replication and envelope protein expression as well as on viral particle secretion, infectivity, and sensitivity to neutralizing antibodies. Our results indicate that several glycans play an important role in HCVcc assembly and/or infectivity. Furthermore, our data demonstrate that at least five glycans on E2 (denoted E2N1, E2N2, E2N4, E2N6, and E2N11) strongly reduce the sensitivity of HCVcc to antibody neutralization, with four of them surrounding the CD81 binding site. Altogether, these data indicate that the glycans associated with HCV envelope glycoproteins play roles at different steps of the viral life cycle. They also highlight differences in the effects of glycosylation mutations between the HCVpp and HCVcc systems. Furthermore, these carbohydrates form a “glycan shield” at the surface of the virion, which contributes to the evasion of HCV from the humoral immune response.

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Protective role of amantadine in mitochondrial dysfunction and oxidative stress mediated by hepatitis C virus protein expression

Biochemical Pharmacology ◽

10.1016/j.bcp.2014.03.018 ◽

2014 ◽

Vol 89 (4) ◽

pp. 545-556 ◽

Cited By ~ 8

Author(s):

Giovanni Quarato ◽

Rosella Scrima ◽

Maria Ripoli ◽

Francesca Agriesti ◽

Darius Moradpour ◽

...

Keyword(s):

Oxidative Stress ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Protein Expression ◽

Mitochondrial Dysfunction ◽

Protective Role ◽

Virus Protein ◽

And Oxidative Stress

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Interferon lambda 4 impacts broadly on hepatitis C virus diversity

10.1101/305151 ◽

2018 ◽

Author(s):

M Azim Ansari ◽

Elihu Aranday-Cortes ◽

Camilla LC Ip ◽

Ana da Silva Filipe ◽

Lau Siu Hin ◽

...

Keyword(s):

Hepatitis C Virus ◽

Viral Load ◽

Hepatitis C ◽

Amino Acid ◽

Active Form ◽

Hcv Infection ◽

Virus Diversity ◽

Genome Wide ◽

Amino Acid Diversity

AbstractType III interferons (IFN-λ) are part of the innate immune response to hepatitis C virus (HCV) infection however the specific role of IFN-λ4 and the nature of the viral adaption to this pressure have not been defined. Here we use paired genome-wide human and viral genetic data in 485 patients infected with HCV genotype 3a to explore the role of IFN-λ4 on HCV evolution during chronic infection. We show that genetic variations within the host IFNL4 locus have a broad and systematic impact on HCV amino acid diversity. We also demonstrate that this impact is larger in patients producing a more active form of IFN-λ4 protein compared to the less active form. A similar observation was noted for viral load. We conclude that IFN-λ4 protein is a likely causal agent driving widespread HCV amino acid changes and associated with viral load and possibly other clinical and biological outcomes of HCV infection.

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