Abstract
Background and AimsHepatitis C virus (HCV) infection is a challenge to prevent and treat because of the rapid development of drug resistance and escape. Viral entry is required for initiation, spread, and maintenance of infection, making it an attractive target for antiviral strategies.MethodsUsing genetic immunization, we produced four monoclonal antibodies (mAbs) against the HCV host entry factor CD81. The effects of antibodies on inhibition of HCV infection and dissemination were analyzed in HCV permissive human liver cell lines.ResultsThe anti-CD81 mAbs efficiently inhibited infection by HCV of different genotypes as well as a HCV escape variant selected during liver transplantation and re-infecting the liver graft. Kinetic studies indicated that anti-CD81 mAbs target a post-binding step during HCV entry. In addition to inhibiting cell-free HCV infection, one antibody was also able to block neutralizing antibody-resistant HCV cell-cell transmission and viral dissemination without displaying any detectable toxicity.ConclusionA novel anti-CD81 mAb generated by genetic immunization efficiently blocks HCV spread and dissemination. This antibody will be useful to further unravel the role of virus-host interactions during HCV entry and cell-cell transmission. Furthermore, this antibody may be of interest for the development of antivirals for prevention and treatment of HCV infection.
Highlights
Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide
Inhibition of HCV infection by anti-CD81 monoclonal antibodies. To investigate whether these antibodies inhibit HCV infection, Huh7.5.1 cells were pre-incubated with anti-CD81 mAbs and infected with chimeric luciferase reporter virus Luc-Jc1
To investigate whether anti-CD81 mAbs were effective against other HCV genotypes, we analyzed their inhibition of HCVpp bearing envelope glycoproteins from HCV genotype 1b
Summary
The current therapy against HCV infection based on pegylated interferon-alfa (PEG-IFN-a) and ribavirin does not allow to cure all patients. The addition of a direct-acting antiviral (DAA) targeting HCV protein processing - telaprevir or boceprevir- to the standard of care improves sustained virological response in genotype 1 infected patients, toxicity of the individual compounds and development of viral resistance remain major challenges [1]. A vaccine is not available and the absence of preventive strategies is a major limitation for patients undergoing liver transplantation (LT) for HCV-related end-stage liver disease. Hepatitis C virus (HCV) infection is a challenge to prevent and treat because of the rapid development of drug resistance and escape. Viral entry is required for initiation, spread, and maintenance of infection, making it an attractive target for antiviral strategies
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