Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection

Abstract

SUMMARY The role that broadly neutralizing antibodies (bNAbs) play in natural clearance of human hepatitis C virus (HCV) infection and the underlying mechanisms remain unknown. Here, we investigate the mechanism by which bNAbs, isolated from two humans who spontaneously cleared HCV infection, contribute to HCV control. Using viral gene sequences amplified from longitudinal plasma of the two subjects, we found that these bNAbs, which target the front layer of the HCV envelope protein E2, neutralized most autologous HCV strains. Acquisition of resistance to bNAbs by some autologous strains was accompanied by progressive loss of E2 protein function, and temporally associated with HCV clearance. These data demonstrate that bNAbs can mediate clearance of human HCV infection by neutralizing infecting strains and driving escaped viruses to an unfit state. These immunopathologic events distinguish HCV from HIV-1 and suggest that development of an HCV vaccine may be achievable.

Cholesterol sensing by CD81 is important for hepatitis C virus entry

“…Binding of the E2 glycoprotein of hepatitis C virus (HCV) to the large extracellular loop of CD81 is a defining event in the entry of HCV [1] and is targeted by multiple broadly neutralising antibodies; thus placing this molecular interaction at the forefront of current HCV vaccine development [2,3]. Whilst the importance of CD81 in HCV entry is well established, the precise details of E2-CD81 interaction have yet to be defined and the molecular determinants of CD81 receptor activity are only partially understood [4].…”

Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development

“…Previous studies have shown that accumulation of affinity-enhancing mutations is critical for eventual control of viremia during chronic LCMV infection (Chen et al, 2018;Chou et al, 2016). However, the delayed production of neutralizing antibody during chronic LCMV infection (Battegay et al, 1993;Eschli et al, 2007) suggests that the process of affinity maturation is dysregulated, an alteration that may also occur during other chronic infections (Doria-Rose et al, 2014;Kinchen et al, 2018;Minamitani et al, 2015;Wu et al, 2015). Based on the data above showing reduced numbers of LCMV-specific GC B cells during chronic infection but increased numbers of LCMV-specific PC, we hypothesized that 9 chronic infection might increase the overall quantity of LCMV-specific antibodies but impair affinity maturation and therefore serum antibody avidity.…”

“…Moreover, chronic viral infections in mice and humans can result in lymphoid tissue disruption and/or fibrosis (Mueller et al, 2007;Schacker et al, 2006;Wilson et al, 2013), perhaps impacting B cell responses. However, despite these challenges, GC still form during chronic infection (Barnett et al, 2016;Daugan et al, 2016) and antibodies have been shown to diversify over time during chronic HIV and HCV infections (Doria-Rose et al, 2014;Kinchen et al, 2018;Wu et al, 2015), suggesting ongoing GC activity. Moreover, despite generally smaller GCs during chronic infection, affinity-matured antibodies produced as a result of the GC response exert partial but critical control of viral replication and, in some cases, lead to viral control (Chen et al, 2018;Chou et al, 2016;Doria-Rose et al, 2014;Kinchen et al, 2018).…”

“…However, despite these challenges, GC still form during chronic infection (Barnett et al, 2016;Daugan et al, 2016) and antibodies have been shown to diversify over time during chronic HIV and HCV infections (Doria-Rose et al, 2014;Kinchen et al, 2018;Wu et al, 2015), suggesting ongoing GC activity. Moreover, despite generally smaller GCs during chronic infection, affinity-matured antibodies produced as a result of the GC response exert partial but critical control of viral replication and, in some cases, lead to viral control (Chen et al, 2018;Chou et al, 2016;Doria-Rose et al, 2014;Kinchen et al, 2018). Additionally, non-neutralizing antibodies are required to partially contain infection in many cases (Barnett et al, 2016;Hangartner et al, 2006;Horwitz et al, 2017;Richter and Oxenius, 2013;Straub et al, 2013) and can apply selective pressure for viral escape and evolution in some settings (Doria-Rose et al, 2014;Kinchen et al, 2018;Wu et al, 2015).…”

“…Moreover, despite generally smaller GCs during chronic infection, affinity-matured antibodies produced as a result of the GC response exert partial but critical control of viral replication and, in some cases, lead to viral control (Chen et al, 2018;Chou et al, 2016;Doria-Rose et al, 2014;Kinchen et al, 2018). Additionally, non-neutralizing antibodies are required to partially contain infection in many cases (Barnett et al, 2016;Hangartner et al, 2006;Horwitz et al, 2017;Richter and Oxenius, 2013;Straub et al, 2013) and can apply selective pressure for viral escape and evolution in some settings (Doria-Rose et al, 2014;Kinchen et al, 2018;Wu et al, 2015). Thus, humoral immune responses that occur during chronic infections likely involve considerable participation of GC B cell responses.…”