KSHV vIL6 Inhibits Functional B Cell Maturation During De Novo Infection.

Despite causative links to lymphoproliferative disorders, little is known about early events governing KSHV infection in B lymphocytes. IL-6 signaling plays a critical role in KSHV-mediated disease, with human IL-6 (hIL6) levels correlating with viral load and disease progression. This dynamic is even more complex due to the coexistence of hIL6 and KSHV-encoded viral IL-6 (vIL6) in these diseases. We hypothesize that hIL6 and vIL6 play critical, separable and collective roles in the early stages of KSHV infection in B cells. In this study, we use our ex vivo model of KSHV infection in human tonsil lymphocytes to investigate the relative contributions of vIL6 and hIL6 to early infection events in human B cells. We demonstrate that vIL6 and hIL6 collectively suppress KSHV infection in B cells restricting the distribution of KSHV within B cell subsets. We show that vIL6 manipulates hIL6 expression in a subset-specific manner, and that vIL6 and hIL6 differentially influence the differentiation of germinal center and plasmablasts. Taken together, these results suggest a novel paradigm in which KSHV uses vIL6 to abrogate the GC-mediated maturation pathway for antibody secreting cells that is driven by hIL6 signaling.