Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation

Fafi‐Kremer, Samira; Fofana, Isabel; Soulier, Eric; Carolla, P.; Meuleman, Philip; Leroux‐Roels, Geert; Patel, Arvind H.; Cosset, François‐Loïc; Pessaux, Patrick; Doffoël, Michel; Wolf, Philippe; Stoll‐Keller, Françoise; Baumert, Thomas F.

doi:10.1084/jem.20090766

Cited by 122 publications

(171 citation statements)

References 48 publications

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“…5,6 Thus, it represents a prototype variant that may be largely refractory to immunopreventive approaches or vaccines. We first generated VL:JFH1 HCVcc by cotransfecting HCV RNA alone, with a scrambled nucleotide control (siCtrl), or with siRNA that targets apoE expression (siApoE).…”

Section: Resultsmentioning

confidence: 99%

“…Clearly, the development of an effective vaccine requires a detailed understanding of viral evasion from host immune responses, including nAbs. Previous studies investigating the molecular mechanisms of HCV liver graft infection, identified a viral variant termed VL 5,6 with efficient escape from patient nAbs. 5,6 Functional genetics had identified phenylalanine at HCV polyprotein residue 447 as being important for neutralization escape.…”

Section: H Epatitis C Virus (Hcv) Is a Major Health Problem Infectingmentioning

confidence: 99%

“…Previous studies investigating the molecular mechanisms of HCV liver graft infection, identified a viral variant termed VL 5,6 with efficient escape from patient nAbs. 5,6 Functional genetics had identified phenylalanine at HCV polyprotein residue 447 as being important for neutralization escape. 6 This amino acid is widely conserved among HCV isolates, as shown by its prevalence of 98.4% in all genotypes (including Jc1, Japanese fulminant hepatitis virus [JFH1], and H77) and 96.2% in genotype 1b strains (including VL).…”

Section: H Epatitis C Virus (Hcv) Is a Major Health Problem Infectingmentioning

confidence: 99%

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Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies

et al. 2016

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BACKGROUND & AIMS:Efforts to develop an effective vaccine against hepatitis C virus (HCV) have been hindered by the propensity of the virus to evade host immune responses. HCV particles in serum and in cell culture associate with lipoproteins, which contribute to viral entry. Lipoprotein association has also been proposed to mediate viral evasion of the humoral immune response, though the mechanisms are poorly defined. METHODS: We used small interfering RNAs to reduce levels of apolipoprotein E (apoE) in cell cultureÀderived HCVÀproducing Huh7.5-derived hepatoma cells and confirmed its depletion by immunoblot analyses of purified viral particles. Before infection of naïve hepatoma cells, we exposed cell cultureÀderived HCV strains of different genotypes, subtypes, and variants to serum and polyclonal and monoclonal antibodies isolated from patients with chronic HCV infection. We analyzed the interaction of apoE with viral envelope glycoprotein 2 and HCV virions by immunoprecipitation. RESULTS: Through loss-of-function studies on patient-derived HCV variants of several genotypes and subtypes, we found that the HCV particle apoE allows the virus to avoid neutralization by patient-derived antibodies. Functional studies with human monoclonal antiviral antibodies showed that conformational epitopes of envelope glycoprotein 2 domains B and C were exposed after depletion of apoE. The level and conformation of virion-associated apoE affected the ability of the virus to escape neutralization by antibodies. CONCLUSIONS: In cell-infection studies, we found that HCV-associated apoE helps the virus avoid neutralization by antibodies against HCV isolated from chronically infected patients. This method of immune evasion poses a challenge for the development of HCV vaccines.

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Section: Resultsmentioning

confidence: 99%

Section: H Epatitis C Virus (Hcv) Is a Major Health Problem Infectingmentioning

confidence: 99%

Section: H Epatitis C Virus (Hcv) Is a Major Health Problem Infectingmentioning

confidence: 99%

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Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies

et al. 2016

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“…Indeed, HCV is known to evade humoral immune responses, as indicated by a lack of resistance to HCV reinfection in i.v. drug users (13), HCV reinfection during liver transplantation (14), and an ongoing difficulty of developing effective vaccines. The role of exosomes in HCV infection is still largely unknown.…”

mentioning

confidence: 99%

Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells

Ramakrishnaiah

Thumann

Fofana

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Recent evidence indicates there is a role for small membrane vesicles, including exosomes, as vehicles for intercellular communication. Exosomes secreted by most cell types can mediate transfer of proteins, mRNAs, and microRNAs, but their role in the transmission of infectious agents is less established. Recent studies have shown that hepatocyte-derived exosomes containing hepatitis C virus (HCV) RNA can activate innate immune cells, but the role of exosomes in the transmission of HCV between hepatocytes remains unknown. In this study, we investigated whether exosomes transfer HCV in the presence of neutralizing antibodies. Purified exosomes isolated from HCV-infected human hepatoma Huh7.5.1 cells were shown to contain full-length viral RNA, viral protein, and particles, as determined by RT-PCR, mass spectrometry, and transmission electron microscopy. Exosomes from HCV-infected cells were capable of transmitting infection to naive human hepatoma Huh7.5.1 cells and establishing a productive infection. Even with subgenomic replicons, lacking structural viral proteins, exosome-mediated transmission of HCV RNA was observed. Treatment with patient-derived IgGs showed a variable degree of neutralization of exosome-mediated infection compared with free virus. In conclusion, this study showed that hepatic exosomes can transmit productive HCV infection in vitro and are partially resistant to antibody neutralization. This discovery sheds light on neutralizing antibodies resistant to HCV transmission by exosomes as a potential immune evasion mechanism.

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“…GP E2 is the main target of neutralizing antibodies (nAbs) in HCV-infected patients and a potent immunogen. Although several monoclonal antibodies (mAbs) targeting this protein have been shown to prevent HCV infection in animal models [4], the high variability of HCV envelope glycoproteins (GPs) enables the virus to efficiently escape nAbs [5].…”

mentioning

confidence: 99%

Unraveling hepatitis C virus structure

Fauvelle¹,

Felmlee²,

Baumert³

2014

Cell Res

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Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation

Cited by 122 publications

References 48 publications

Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies

Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies

Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells

Unraveling hepatitis C virus structure

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