KSHV induces immunoglobulin rearrangements in mature B lymphocytes

Kaposi sarcoma herpesvirus (KSHV/HHV-8) is a B cell tropic human pathogen, which is present in vivo in monotypic immunoglobulin lambda (Ig lambda) light chain but polyclonal B cells. In the current study, we use cell sorting to infect specific B cell lineages from human tonsil specimens in order to examine the immunophenotypic alterations associated with KSHV infection. We describe IL-6 dependent maturation of naive B lymphocytes in response to KSHV infection and determine that the Ig lambda monotypic bias of KSHV infection in vivo is due to viral induction of BCR revision. Infection of immunoglobulin k (Ivk) naive B cells induces expression of Ig lambda and isotypic inclusion, with eventual loss of Igk. We show that this phenotypic shift occurs via re-induction of Rag-mediated V(D)J recombination. These data explain the selective presence of KSHV in Ig lambda B cells in vivo and provide the first evidence that a human pathogen can manipulate the molecular mechanisms responsible for immunoglobulin diversity.