Association of anti-E1E2 antibodies with spontaneous recovery or sustained viral response to therapy in patients infected with hepatitis C virus

Abstract

The monoclonal antibody (mAb) D32.10 recognizes a discontinuous epitope encompassing three regions E1 (amino acids 297-306), E2A (amino acids 480-494), and E2B (amino acids 613-621) juxtaposed on the surface of serum-derived hepatitis C virus (HCV) particles (HCVsp). The mAb D32.10 inhibits efficiently and specifically the binding of HCVsp to human hepatocytes. Therefore, we investigated the clinical relevance of anti-E1E2A,B response in the serum of patients infected with HCV. To this end, an enzymelinked immunosorbent assay (ELISA) using synthetic E1-, E2A-, and E2B-derived peptides was used. The ELISA was validated in terms of sensitivity, specificity, and test efficiency. The detection of the anti-E1E2 D32.10 epitope-binding antibodies during natural HCV infection in more than 300 HCV-positive sera demonstrated significantly (P < 0.001) higher prevalence of these antibodies: (1) in patients who spontaneously cured HCV infection (46 of 52, 88.5%) showing high titers (70% ! 1/1000) compared to never-treated patients with chronic hepatitis C (7 of 50, 14%) who actively replicated the virus, and (2) in complete responders (20 of 52, 38.5%) who cleared virus following treatment and achieved a sustained viral response compared to nonresponders (4 of 40, 10%). Serum anti-E1E2 antibodies were monitored before, during, and after the current standard-ofcare therapy (pegylated interferon plus ribavirin) in responder and nonresponder patients. Optimal cutoff values were assessed by receiver operating characteristic curve analysis. One month prior to therapy initiation, the threshold of 1131 (optical density 3 1000) gave 100% and 86% positive and negative predictive values, respectively, for achieving or not achieving a sustained viral response. Conclusion: The anti-E1E2 D32.10 epitope-binding antibodies are associated with control of HCV infection and may represent a new relevant prognostic marker in serum. This unique D32.10 mAb may also have immunotherapeutic potential. (HEPATOLOGY 2010;52:1531-1542

Characterization of Periplasmic Protein BP26 Epitopes of Brucella melitensis Reacting with Murine Monoclonal and Sheep Antibodies

“…Optimal cutoff values were defined using the highest sum of sensitivity and specificity. For each optimal cutoff value, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated [33]. P value was obtained for comparing the differences between the areas under ROC curve (AUC) and reference (0.5) by the Kolmogorov-Smirnov Z analysis in SPSS software version 13.0.…”

Neutralizing Antibodies and Pathogenesis of Hepatitis C Virus Infection

“…These antibodies inhibit interactions between E2 and either CD81 [34] or heparan sulfate [42]. Recently, conformational and widely conserved epitopes were identified in E1 and E2 [38,43,44,45]. The human mAb AR3, which defines one of these epitopes (aa 396–424; 436–447; 523–540), neutralizes genetically diverse HCV isolates and protects against challenge of heterologous HCV quasispecies in a human liver–chimeric mouse model [38].…”

“…The human mAb AR3, which defines one of these epitopes (aa 396–424; 436–447; 523–540), neutralizes genetically diverse HCV isolates and protects against challenge of heterologous HCV quasispecies in a human liver–chimeric mouse model [38]. Similar antibodies recognizing conformational epitopes, in this case defined by the mouse mAb D32.10 (aa 297–306; 480–494 and 613–621), were observed to circulate at high levels in the sera of patients with resolved HCV infection [44,45]. …”

Development and characterization of a human monoclonal antibody targeting the N-terminal region of hepatitis C virus envelope glycoprotein E1

“…The early generation of neutralizing antibodies has been associated with resistance to infection in individuals at high-risk of exposure, spontaneous clearance during acute infection and sustained virologic response after therapy (Ndongo et al, 2010; Osburn et al, 2014; Swann et al, 2016). Although the envelope of HCV contains multiple immunogenic epitopes, the majority of monoclonal antibodies (mAbs) isolated from infected patients or vaccinated animals have been identified as E2-specific (Tabll et al, 2015).…”