Biased IGH VDJ gene repertoire and clonal expansions in B cells of chronically hepatitis C virus-infected individuals

Patients chronically infected with hepatitis C virus (HCV) frequently develop mixed cryoglobulinemia (MC), a monoclonal expansion of IgM+ autoreactive B cells, and also have an increased B cell lymphoma risk. Whether HCV infection also impacts the B cell compartment and the B cell receptor repertoire in patients not affected by MC or lymphomas is poorly understood. For 22 HCV+ patients and 7 healthy controls, we performed high throughput sequencing of immunoglobulin heavy chain V region genes of naive, mature CD5+, IgM+ memory, and class-switched memory B cells. An increased usage of several IGHV segments, including IGHV1-69 and IGHV4-59, which are closely linked to MC and HCV-associated lymphomas, was specifically seen among IgM+ memory B cells of the patients. Moreover, many, and partly very large, expanded clones were seen predominantly among IgM+ memory B cells of all HCV-infected patients analysed. Thus, chronic HCV infection massively disturbs the B cell compartment even in patients without clinically detectable B cell lymphoproliferation.