Mutations That Alter Use of Hepatitis C Virus Cell Entry Factors Mediate Escape From Neutralizing Antibodies

Inserm, U748, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Gastroenterology (Impact Factor: 16.72). 04/2012; 143(1):223-233.e9. DOI: 10.1053/j.gastro.2012.04.006
Source: PubMed


The development of vaccines and other strategies to prevent hepatitis C virus (HCV) infection is limited by rapid viral evasion. HCV entry is the first step of infection; this process involves several viral and host factors and is targeted by host-neutralizing responses. Although the roles of host factors in HCV entry have been well characterized, their involvement in evasion of immune responses is poorly understood. We used acute infection of liver graft as a model to investigate the molecular mechanisms of viral evasion.
We studied factors that contribute to evasion of host immune responses using patient-derived antibodies, HCV pseudoparticles, and cell culture-derived HCV that express viral envelopes from patients who have undergone liver transplantation. These viruses were used to infect hepatoma cell lines that express different levels of HCV entry factors.
By using reverse genetic analyses, we identified altered use of host-cell entry factors as a mechanism by which HCV evades host immune responses. Mutations that alter use of the CD81 receptor also allowed the virus to escape neutralizing antibodies. Kinetic studies showed that these mutations affect virus-antibody interactions during postbinding steps of the HCV entry process. Functional studies with a large panel of patient-derived antibodies showed that this mechanism mediates viral escape, leading to persistent infection in general.
We identified a mechanism by which HCV evades host immune responses, in which use of cell entry factors evolves with escape from neutralizing antibodies. These findings advance our understanding of the pathogenesis of HCV infection and might be used to develop antiviral strategies and vaccines.

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Available from: Francois habersetzer, Dec 17, 2013
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    • "Mutations in the GPs confer viral escape to humoral responses by altering the use of the host cell receptors Fofana I. et al., Gastroenterology 2012 HCV genetic variability allows the virus its adaptation to the host "
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    • "Mutations that alter use of the CD81 receptor also allowed the virus to escape neutralizing antibodies. These experiments replicate the mechanism of viral infection, mediating viral escape and leading to persistent infection in general [Fofana et al., 2012]. "
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    • "We have previously demonstrated that viral entry is a key determinant for HCV re-infection during LT and that HCV-CD81 interactions play an important role in this process [8], [46]. Moreover, we have demonstrated that receptor-specific antibodies or kinase inhibitors specifically inhibit entry of highly infectious HCV escape variants that are resistant to autologous host responses and re-infect the liver graft [8], [9], [25], [38]. "
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