Neutralizing antibodies

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Viral attachment and entry is a major target of adaptive host cell defences. Viral proteins are recognized as non-self by the host’s immune system and induce the production of antibodies. A small proportion of these antibodies exhibit antiviral activity in vitro and are defined as virus-neutralizing antibodies. These antibodies render virions non-infectious by interfering with receptor binding and cell entry. Many successful antiviral vaccines are based on the induction of neutralizing antibodies. Isolation and characterization of antibodies targeting distinct steps of HCV entry is an important strategy for protection against this virus and provide a rational basis for HCV vaccine development. Antibody-mediated neutralization occurs during HCV infection in vivo but the role of antibodies for the control of HCV infection is still unclear. Antibodies with HCV neutralizing properties have been first described in experimental infection of chimpanzees (81, 82). These antibodies were directed against epitopes in the hypervariable region (HVR-1) of HCV envelope glycoprotein E2 and appeared to be isolate-specific (81, 82). The presence of antibodies directed against HVR-1 has also been associated with viral clearance in HCV-infected humans (83) and HCV-infected patients with primary antibody deficiencies have been reported to have accelerated rates of disease progression (84, 85). However, HCV infection is established despite the induction of an humoral immune response that targets various epitopes of the HCV envelope glycoproteins (26, 27, 86-88). Until recently, functional studies analyzing the neutralizing antibody response during acute and chronic HCV infection using HCV model systems demonstrated a lack of neutralizing antibodies in the majority of patients with acute HCV infection (26, 27, 86, 89). These studies were limited by the fact that the viral surrogate ligand was derived from a different isolate than the virus present in the infected patient thus precluding the detection of isolate-specific antibodies. Most recently, studies using well defined nosocomial or single-source HCV outbreaks with a defined inoculum enabled for the first time to study the role of isolate-specific neutralizing antibodies for HCV clearance in humans. Using the HCVpp model system, two studies demonstrated that neutralizing antibodies are induced in the early phase of infection by patients who subsequently clear the virus  (90) or control viral infection (60). These results suggest that a strong early neutralizing antibody response may play a role in the outcome of HCV infection. Patients who do not clear the virus develop high-titer and even cross-neutralizing antibodies during the chronic phase of infection (9, 26, 27, 86, 90). Viral escape from antibody-mediated neutralization in these individuals may occur on several levels: (i) HCV exists as a quasispecies with distinct viral variants in infected individuals changing constantly over time and his variability has been shown to represent a mechanism of escape from antibody-mediated neutralization in the chimpanzee model (27); (ii) the interplay of HCV glycoproteins with high-density lipoprotein and the scavenger receptor BI has been shown to mediate protection from neutralizing antibodies present in sera of acute and chronic HCV-infected patients (61, 91); and (iii) as shown for other viruses such as HIV, escape from neutralizing antibodies may occur through a combination of different mechanisms, for instance point mutations, insertions/deletions or changes in glycosylation patterns of the viral envelope (92) or conformational masking of receptor binding sites following envelope-antibody interaction (93) preventing neutralizing antibody binding. The HCV tissue culture model systems and patient cohorts with well defined viral isolates will now allow to adress these questions and define therapeutic strategies based on neutralizing antibodies. Several viral epitopes targeted by neutralizing antibodies have already been identified: epitopes of the E2 HVR-1 region (aa 384-410) (18, 25, 61), an epitope adjacent to the N-terminal region HVR-1 region (aa 408-422) (26, 94), the E2 CD81 binding region (aa 474-494 and aa 522-551) (18, 47, 94) and conformational epitopes within glycoprotein E2 (95, 96). These epitopes may represent potential candidate targets for antibodies in passive immunoprophylaxis. Indeed, two studies have demonstrated that monoclonal antibodies directed against conformational epitopes (95) or epitope aa 412-423 exhibited broad cross-neutralizing activity among all major genotypes of HCVpp entry (94) as well as HCVcc infectivity (97). Future in vivo studies are required to study the relevance of these findings for antibody-mediated prevention of HCV infection. This may have important implications for the development of novel preventive and curative antiviral strategies, e. g. passive immunoprophylaxis after accidental exposure to HCV and prevention of reinfection of liver grafts after liver transplantation.