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Broad Anti-Hepatitis C Virus (HCV) Antibody Responses Are Associated with Improved Clinical Disease Parameters in Chronic HCV Infection
Swann RE, et al.
HeJ. Virology 2016, 90; 9:4530-43.

During HCV infection, broadly neutralizing antibody (bNAb) responses targeting E1E2 envelope glycoproteins 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 HLADQB1 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.

Expert's Commentary

« Host immune response to early HCV infection is driven by innate cellular responses and is a primary determinant of progression to chronic infection. Emerging evidence also supports the protective role of neutralizing antibodies and the ability of humoral response to modify the course of infection at the acute to chronic transition. Here the authors report on the association of bNAb with clinically relevant outcomes including HCV viral load and surrogates of fibrosis using transient elastrography. Generally HCV viral load is not associated with severity of liver disease or risk of cirrhosis and here it is unclear the clinical significance of the differences noted in HCV viral load by level of bNAb binding. However, the association of bNAb binding breadth in the genotype 1 subgroup with transient elastrography is intriguing. What is unclear is whether the higher stiffness (kPa) scores are related to inflammation or fibrosis, because here the authors assume that stiffness only reflects fibrosis. In fact, the very high elastography results for almost half of the narrow breadth cohort raises the question as to what is represented in these numbers. Use of liver biopsy would have been more ideal for this type of exploratory study because both inflammation and fibrosis can be independently assessed. Future studies assessing the association of bNAb and relapse after HCV therapy would be of great interest as we have yet to understand the mechanisms of relapse but is likely at least in part to be directly related to host immune response and viral control »

Dr Susanna Naggie