KSHV/HHV-8 primary infection and scenario for the generation of an infected B-cell reservoir and Castleman lesions. (A) Infection via saliva of subepithelial tonsillar dendritic cell–specific intercellular adhesion molecule-3-grabbing nonintegrin–rich naive B cells. (B) Early and transient prelatent “lytic burst” transcription program and possible detection of episome-associated LANA⁺ cells by day 5 postinfection. (C) Blasting, dividing, and proliferation of the infected cells; BCR revision and editing for a shift toward λ-chain expression. (D) At that point, and as other herpesviruses, KSHV/HHV-8 have to exhibit a specific strategy to escape immune surveillance and constitute an KSHV/HHV-8 reservoir. The exact phenotype of the putative long-lived B cells constitutive of the KSHV/HHV-8 reservoir remains unknown. (E) Induction of a lytic cycle with production of vIL-6 is probably crucial for KSHV/HHV-8–infected cells to generate the MCD lesions observed in lymphoid organs. miRNA, microRNA; PAN RNA, polyadenylated nuclear RNA; RTA, replication and transcription activator; vCYC, viral cyclin.