Characteristics of circulating KSHV-infected viroblasts during active KSHV+ multicentric Castleman disease

Kaposi Sarcoma-associated herpesvirus/ Human Herpesvirus 8 (KSHV/HHV8) associated multicentric Castleman disease (MCD) is a polyclonal B cell lymphoproliferative disorder mainly occurring in immunocompromised hosts. The diagnosis relies on lymph node biopsy demonstrating KSHV infected cells located in the mantle zone with a marked interfollicular plasma-cell infiltration. Infected cells are large cells positive for IgM,  light chain, and CD38, described initially as infected "plasmablasts". We show that IgM+λ+CD38high cells were also detectable in the peripheral blood of 14/18 (78%) patients with active KSHV-MCD and absent from 40 controls. Using immunofluorescence and flow-FISH, we demonstrate that these cells are KSHV infected and expressed both latent and lytic KSHV transcripts. These KSHV infected viroblasts (KIV) harbor a distinct phenotype compared to conventional plasmablasts. We also identified several putative mechanisms of immune escape used by KSHV, as KIV displayed an overall decrease of co-stimulatory molecules with a remarkable lack of CD40 expression and are IL-10 producing cells. The identification of this specific and easily accessible KSHV+ circulating population brings new elements in the understanding of KSHV-MCD but also raises new questions that need to be clarified.