Abstract
Despite the production of neutralizing antibodies to hepatitis C virus (HCV), many patients fail to clear the virus and instead develop chronic infection and long-term complications. To understand how HCV infection perturbs the antibody repertoire and to identify molecular features of antibody genes associated with either viral clearance or chronic infection, we sequenced the V(D)J region of naïve and memory B cells of 6 persons who spontaneously resolved an HCV infection (SR), 9 patients with a newly diagnosed chronically evolving infection (CE), and 7 healthy donors. In both naïve and memory B cells, the frequency of use of particular antibody gene subfamilies and segments varied among the three clinical groups, especially between SR and CE. Compared to CE, SR antibody genes used fewer VH, D and JH gene segments in naïve B cells and fewer VH segments in memory B cells. SR and CE groups significantly differed in the frequency of use of 7 gene segments in naïve B cell clones and 3 gene segments in memory clones. The nucleotide mutation rates were similar among groups, but the pattern of replacement and silent mutations in memory B cell clones indicated greater antigen selection in SR than CE. Greater clonal evolution of SR than CE memory B cells was revealed by analysis of phylogenetic trees and CDR3 lengths. Pauciclonality of the peripheral memory B cell population is a distinguishing feature of persons who spontaneously resolved an HCV infection. This finding, previously considered characteristic only of patients with HCV-associated lymphoproliferative disorders, suggests that the B cell clones potentially involved in clearance of the virus may also be those susceptible to abnormal expansion.
Highlights
Deciphering the humoral immune response to hepatitis C virus (HCV) has been challenging
To understand if and how HCV infection perturbs B cell antigen receptor repertoire and how this is associated with the outcome of HCV infection, we cloned and sequenced the V(D)J region of circulating CD272 and CD27+ B cells from 7 healthy donors (HD), 6 persons who spontaneously resolved (SR) an HCV infection, and 9 patients with chronically evolving (CE) HCV infection (Table 1)
In memory B cell clones (Figure 1B), the pattern of prevalent VH1 and VH3, followed by VH5, was maintained a small percentage of clones used VH6 and VH7; statistical significance was observed for the comparison between HD and SR (p = 0.027, attributable to VH1 and VH5), but not for HD vs. chronically evolving infection (CE) (p = 0.24) or SR vs. CE (p = 0.11)
Summary
Deciphering the humoral immune response to hepatitis C virus (HCV) has been challenging. Virus-specific antibodies are produced in essentially all persons infected with HCV, about 80% of these patients develop persistent infection and are at risk of long-term complications [1,2]. The most prevalent of these complications are liver cirrhosis and hepatocellular carcinoma [3], but HCV-infected persons may develop mixed cryoglobulinemia (MC) and B cell non-Hodgkin lymphoma (B-NHL) [4,5,6]. It is thought that B cells are largely ineffective in resolving HCV infection while they are responsible for its lymphoproliferative complications. Greater understanding of the B cell response to HCV may help predict the outcome of the infection in individual patients as well as their risk of developing lymphoproliferative disorders. Studying the B cell (antibody) response to HCV has been extremely difficult due to the heterogeneous nature of HCV, the lack of a practical and readily available cell culture system to screen antibodies, and the limited resources for studying HCV infection in chimpanzees, the only species susceptible to HCV infection other than humans [7]
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