Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C

Abstract

In contrast to a detailed understanding of antiviral cellular immune responses, the impact of neutralizing antibodies for the resolution of acute hepatitis C is poorly defined. The analysis of neutralizing responses has been hampered by the fact that patient cohorts as well as hepatitis C virus (HCV) strains are usually heterogeneous, and that clinical data from acute-phase and long-term follow-up after infection are not readily available. Using an infectious retroviral HCV pseudoparticle model system, we studied a cohort of women accidentally exposed to the same HCV strain of known sequence. In this single-source outbreak of hepatitis C, viral clearance was associated with a rapid induction of neutralizing antibodies in the early phase of infection. Neutralizing antibodies decreased or disappeared after recovery from HCV infection. In contrast, chronic HCV infection was characterized by absent or low-titer neutralizing antibodies in the early phase of infection and the persistence of infection despite the induction of cross-neutralizing antibodies in the late phase of infection. These data suggest that rapid induction of neutralizing antibodies during the early phase of infection may contribute to control of HCV infection. This finding may have important implications for understanding the pathogenesis of HCV infection and for the development of novel preventive and therapeutic antiviral strategies.vaccines ͉ pathogenesis ͉ host reponses

Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance

“…In contrast, approximately 30% of individuals who become infected with HCV spontaneously clear the infection (23), even though the viral diversity in HCV-infected individuals is comparable to or exceeds that of the diversity of HIV isolates in HIV-infected subjects (24)(25)(26)(27). Spontaneous clearance of HCV has been associated with effective innate and T cell responses, but we and others have shown that spontaneous clearance is associated with early appearance of broadly neutralizing antibodies against HCV in serum (28,29). mAbs from individuals with broadly neutralizing serum and clearance of HCV have not been isolated to date, so it is not known whether these mAbs have unique features relative to the mAbs previously isolated from individuals with persistent HCV infection.…”

Hepatitis C virus resistance to broadly neutralizing antibodies measured using replication-competent virus and pseudoparticles

“…Understanding of virus neutralization by antibodies is important for vaccine development, since prior studies have shown that antibodies that neutralize HCV play an important role in immune-mediated control of the virus, and that neutralizing antibody resistance mutations may reduce viral replicative fitness (Gottwein et al, 2009;Lavie et al, 2014;Osburn et al, 2014;Pestka et al, 2007). However, study of HCV neutralizing antibodies has been hindered by lack of standardized methods to measure virus entry and neutralization, and by inadequate genetic diversity in viral panels.…”

“…HCVpp have greatly advanced the understanding of HCV entry and neutralization by antibodies (Giang et al, 2012;Law et al, 2008;Morin et al, 2012;Osburn et al, 2014;Pestka et al, 2007). This model system has been used extensively in identifying HCV cell surface receptors required for viral entry (Bartosch et al, 2003;Cormier et al, 2004;McKeating et al, 2004;Zhang et al, 2004), and studies using HCVpp have established that neutralizing antibodies can drive evolution in vivo of HCV E1E2, leading to neutralization escape (Dowd et al, 2009;Pestka et al, 2007).…”

“…This model system has been used extensively in identifying HCV cell surface receptors required for viral entry (Bartosch et al, 2003;Cormier et al, 2004;McKeating et al, 2004;Zhang et al, 2004), and studies using HCVpp have established that neutralizing antibodies can drive evolution in vivo of HCV E1E2, leading to neutralization escape (Dowd et al, 2009;Pestka et al, 2007). HCVpp panels expressing diverse E1E2 variants have also been used to define neutralizing breadth of antibodies and to show that development of broadly neutralizing antibodies is associated with spontaneous clearance of HCV infection (Osburn et al, 2014;Pestka et al, 2007), and reduced liver fibrosis in chronic infection (Swann et al, 2016).…”

Native Folding of a Recombinant gpE1/gpE2 Heterodimer Vaccine Antigen from a Precursor Protein Fused with Fc IgG

“…nAbs that primarily target the HCV envelope glycoproteins E1 and E2 have been identified during natural HCV infection (7)(8)(9)(10). However, more recent studies have highlighted a protective role for HCV nAbs during the acute phase of infection that are associated with recovery (11)(12)(13).…”