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

Kaposi sarcoma–associated herpesvirus (KSHV)/human herpesvirus 8–associated multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder that mainly occurs 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 immunoglobulin M (IgM), λ light chain, and CD38, described initially as infected plasmablasts. We show that IgM(+)λ(+)CD38(high) cells were also detectable in the peripheral blood of 14 out of 18 (78%) patients with active KSHV-MCD and absent in 40 controls. Using immunofluorescence and flow–fluorescence in situ hybridization, we demonstrate that these cells are KSHV infected and express both latent and lytic KSHV transcripts. These KSHV-infected viroblasts (KIVs) harbor a distinct phenotype compared with conventional plasmablasts. We also identified several putative mechanisms of immune escape used by KSHV, because KIVs displayed an overall decrease of costimulatory molecules, with a remarkable lack of CD40 expression and are interleukin-10–producing cells. The identification of this specific and easily accessible KSHV(+) circulating population brings new elements to the understanding of KSHV-MCD but also raises new questions that need to be clarified.