Early appearance of deep neutralizing antibody responses in persons clearing acute Hepatitis C infection revealed by a representative genotype 1 HCV E1E2 pseudoparticle library
William O. Osburn, Anna E. Snider, Brittany Wells, Rachel Latanich, Justin R. Bailey, David L. Thomas, Andrea Cox, Stuart Ray;
Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
One of the obstacles to investigating the role of neutralizing antibodies (nAbs) in the outcome of acute HCV infection is the unique global and intrapersonal sequence variability of HCV, which complicates selection of a representative sequence. We used a representative genotype 1 HCV pseudoparticle (HCVpp) library to assess nAb responses during acute HCV infection to determine whether infection outcome is associated with the neutralizing antibody (nAb) timing or depth (neutralization of multiple genotype-matched variants). The HCVpp library comprises 19 genetically-distinct genotype 1 HCVpp derived from primary HCV isolates that represent the natural variability of genotype 1 E1E2 sequences. Neutralization of individual library HCVpp by the last viremic plasma sample obtained before clearance was compared to infection duration-matched specimens obtained from subjects who developed persistent infection. Overall, 60.3% of plasma samples neutralized at least one HCVpp in the genotype 1 HCVpp library while the subtype 1a and 1b HCVpp with the highest neutralization sensitivity was neutralized by only 41.3% and 39.7% of subjects, respectively, (subtype 1a, P = 0.05, subtype 1b, P = 0.03) highlighting the utility of using a library screening approach for assessing nAb responses. A trend toward an increased percentage of Clearance subjects neutralizing at least one HCVpp compared to Persistence subjects was observed (76.2% versus 52.4%, P = 0.101). However, the median number of library HCVpp neutralized by Clearance subjects was six-fold greater than Persistence subjects (6 versus 1, P = 0.007). Moreover, the number of library HCVpp neutralized by Persistence subjects increased during acute infection (P < 0.001) while the number of library HCVpp neutralized by Clearance subjects decreased following control of viremia (P = 0.03). Surprisingly, the depth of anti-genotype 1 nAb responses was not different in subjects infected with genotype 1, 2 or 3 viruses (P = 0.78). Interestingly, two single nucleotide polymorphisms in the HLA-DQ locus were associated with nAb depth. Taken together, these data demonstrate that nAb responses are delayed in persistently infected individuals then progressively deepen, whereas in persons who control viremia deep responses are detected early and contract after clearance of viremia, independent of the infection viral genotype. These findings provide further evidence for the role of nAb in controlling HCV infection and highlight the potential benefit of generating deep anti-HCV nAb responses by vaccination.
David L. Thomas - Grant/Research Support: Merck, Gilead
Stuart Ray - Advisory Committees or Review Panels: Abbott Laboratories, Boer-hinger Ingelheim
The following people have nothing to disclose: William O. Osburn, Anna E. Snider, Brittany Wells, Rachel Latanich, Justin R. Bailey, Andrea Cox