Neutralizing antibodies against hepatitis C virus and the emergence of neutralization escape mutant viruses

Abstract

We developed an in vitro assay for antibodies to hepatitis C virus (HCV) that bind to virions and prevent initiation of the replication cycle in susceptible cells in vitro. These antibodies therefore appear to be capable of neutralizing the virus. Using this assay and a standard inoculum of HCV of known infectivity, we have measured the antibody in serial serum samples obtained from the same chronically infected patient over 14 years following onset of his hepatitis. Such antibody was found in sera collected within 5 years of onset of hepatitis but not in later sera. In double immunoprecipitation experiments with anti-human immunoglobulin, the same sera that contained neutralizing antibody were found to contain antibody that bound to HCV to form antigen-antibody complexes immunoprecipitable with anti-human globulin. Similarly, plasma collected from this patient in 1990, 13 years after onset of hepatitis, and which contained HCV that had diverged genetically from the 1977 strain, did not contain antibody capable of neutralizing either the 1977 or the 1990 strain of HCV. However, plasma collected a year later (1991, 14 years after onset of hepatitis) contained neutralizing antibody to the 1990, but not the 1977, strain of HCV. These results suggest that HCV does induce antivirion antibody, as measured by blocking of initiation of the replication cycle of virus in cells and by the formation of immunoprecipitable antigen-antibody complexes but that these antibodies are isolate specific and change over time. Thus, these antivirion antibodies function as neutralizing antibodies and are probably in vitro correlates of the attempt of the host to contain the emergence of neutralization-resistant variants of HCV over time.

Time‐shift experiments and patterns of adaptation across time and space

“…Time-shift experiments are also easily conducted with microorganisms in experimental evolution (Bennett et al 1992;Reboud & Bell 1997;Kassen & Bell 1998;Collins et al 2006;Cooper & Lenski 2010). Furthermore, time-shift experiments are routinely used in the study of parasite-immune system coevolution in infectious diseases (Shimizu et al 1994;Richman et al 2003;Smith et al 2004;Moore et al 2009). More recently, several time-shift experiments have been performed to reveal the coevolutionary interactions driving host parasite interactions (Buckling & Rainey 2002;Decaestecker et al 2007;Koskella & Lively 2007;Gandon et al 2008;Gaba & Ebert 2009;Bérénos et al 2011;Gómez & Buckling 2011;Hall et al 2011;Rode et al 2011;Thrall et al 2012).…”

A focus reduction neutralization assay for hepatitis C virus neutralizing antibodies

“…The E1 and E2 glycoproteins are thought to be the viral attachment proteins and thus the main targets for HCV-neutralizing antibodies; identification of protective epitopes conserved across different strains of HCV is therefore a major challenge in vaccine design. A number of antibodies capable of blocking E2 binding to cells or cell receptors have been described, [5][6][7][8] some of which neutralize HCV entry in animal or cellular models [9,10]. Cell entry has been shown to involve several surface molecules (notably including the tetraspanin CD81 and the SR-BI receptor [11,12]), although further studies are needed to better understand how viral entry occurs and how it might be neutralized.…”

Permissiveness of human biliary epithelial cells to infection by hepatitis C virus

“…In this context, the actual pattern and impact of neutralizing anti-HCV antibodies during the natural course of HCV infection or during antiviral therapy remain subject to debate. [9][10][11] The cellular tropism of HCV is another much-debated topic that may have major implications for the understanding of viral pathogenesis. There is compelling evidence for the hepatotropism of HCV, and adult as well as fetal human and chimpanzee hepatocytes can be infected by HCV.…”