Broad Anti-Hepatitis C Virus (HCV) Antibody Responses Are Associated with Improved Clinical Disease Parameters in Chronic HCV Infection

Abstract

During hepatitis C virus (HCV) infection, broadly neutralizing antibody (bNAb) responses targeting E1E2 envelope glycopro-teins are generated in many individuals. It is unclear if these antibodies play a protective or a pathogenic role during chronic infection. In this study, we investigated whether bNAb responses in individuals with chronic infection were associated with differences in clinical presentation. Patient-derived purified serum IgG was used to assess the breadth of HCV E1E2 binding and the neutralization activity of HCV pseudoparticles. The binding and neutralization activity results for two panels bearing viral envelope proteins representing either an intergenotype or an intragenotype 1 group were compared. We found that the HCV load was negatively associated with strong cross-genotypic E1E2 binding (P ‫؍‬ 0.03). Overall, we observed only a modest correlation between total E1E2 binding and neutralization ability. The breadth of intergenotype neutralization did not correlate with any clinical parameters; however, analysis of individuals with genotype 1 (gt1) HCV infection (n ‫؍‬ 20), using an intragenotype pseudoparticle panel, found a strong association between neutralization breadth and reduced liver fibrosis (P ‫؍‬ 0.006). A broad bNAb response in our cohort with chronic infection was associated with a single nucleotide polymorphism (SNP) in the HLA-DQB1 gene (P ‫؍‬ 0.038), as previously reported in a cohort with acute disease. Furthermore, the bNAbs in these individuals targeted more than one region of E2-neutralizing epitopes, as assessed through cross-competition of patient bNAbs with well-characterized E2 antibodies. We conclude that the bNAb responses in patients with chronic gt1 infection are associated with lower rates of fibrosis and host genetics may play a role in the ability to raise such responses. IMPORTANCEGlobally, there are 130 million to 150 million people with chronic HCV infection. Typically, the disease is progressive and is a major cause of severe liver cirrhosis and hepatocellular carcinoma. While it is known that neutralizing antibodies have a role in spontaneous clearance during acute infection, little is known about their role in chronic infection. In the present work, we investigated the antibody response in a cohort of chronically infected individuals and found that a broadly neutralizing antibody response is protective and is associated with reduced levels of liver fibrosis and cirrhosis. We also found an association between SNPs in class II HLA genes and the presence of a broadly neutralizing response, indicating that antigen presentation may be important for the production of HCV-neutralizing antibodies. H epatitis C virus (HCV) is a significant cause of liver morbidity and mortality worldwide (1). In the majority (75%) of those infected, the infection proceeds to a chronic infection (2). Symptomatic acute HCV infection is rare; therefore, HCV has the potential to spread undetected among those at risk. In countries with a high prevalence, a poor health care i...

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

“…Our work supports prior more limited studies showing that HCVcc and HCVpp with identical E1E2 have similar relative neutralization resistance (Bailey et al, 2015a;Fofana et al, 2012;Swann et al, 2016;Urbanowicz et al, 2015). Importantly, to our knowledge, this is the first study to show this correlation using a diverse panel of human bNAbs targeting distinct epitopes across E1E2 and a large panel of diverse natural E1E2 variants, suggesting that these results are broadly applicable to other E1E2 variants and other antibodies.…”

“…Neutralization results obtained using HCVcc and HCVpp have generally been similar (Fofana et al, 2012;Meunier et al, 2005;Scheel et al, 2008;Swann et al, 2016;Urbanowicz et al, 2015), but comparisons of specific infectivity and neutralization of HCVpp and HCVcc expressing genetically identical E1E2 variants have previously been performed only on a fairly limited basis, and to our knowledge neutralization of E1E2-matched HCVpp and HCVcc has never been compared using a diverse panel of bNAbs targeting distinct epitopes.…”

“…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).…”

A cross‐sectional serum investigation of a clustering hepatitis C virus infection in Southwest China

“…The function of neutralizing antibodies in HCV suppression in vivo was not well understood . It has been reported that antibodies against HCV E2 exerted a protective effect against HCV and contributed to virus clearance . In this study, both the serum E2 antibody level and the HCV neutralizing activity increased with HCV RNA load.…”

Standardized Method for the Study of Antibody Neutralization of HCV Pseudoparticles (HCVpp)

“…These particles have been produced with a variety of E1E2 variants from multiple isolates and genotypes [15]. Diverse HCVpp panels have 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 [10, 11], and reduced liver fibrosis in chronic infection [16]. …”