Analysis of KSHV B lymphocyte lineage tropism in human tonsil reveals efficient infection of CD138+ plasma cells

Despite 25 years of research, the basic virology of Kaposi Sarcoma Herpesviruses (KSHV) in B lymphocytes remains poorly understood. This study seeks to fill critical gaps in our understanding by characterizing the B lymphocyte lineage-specific tropism of KSHV. Here, we use lymphocytes derived from 40 human tonsil specimens to determine the B lymphocyte lineages targeted by KSHV early during de novo infection in ourex vivomodel system. We characterize the immunological diversity of our tonsil specimens and determine that overall susceptibility of tonsil lymphocytes to KSHV infection varies substantially between donors. We demonstrate that a variety of B lymphocyte subtypes are susceptible to KSHV infection and identify CD138+ plasma cells as a highly targeted cell type for de novo KSHV infection. We determine that infection of tonsil B cell lineages is primarily latent with few lineages contributing to lytic replication. We explore the use of CD138 and heparin sulfate proteoglycans as attachment factors for the infection of B lymphocytes and conclude that they do not play a substantial role. Finally, we determine that the host T cell microenvironment influences the course of de novo infection in B lymphocytes. These results improve our understanding of KSHV transmission and the biology of early KSHV infection in a naive human host, and lay a foundation for further characterization of KSHV molecular virology in B lymphocyte lineages. Author summary KSHV infection is associated with cancer in B cells and endothelial cells, particularly in the context of immune suppression. Very little is known about how KSHV is transmitted and how it initially establishes infection in a new host. Saliva is thought to be the primary route of person-to-person transmission for KSHV, making the tonsil a likely first site for KSHV replication in a new human host. Our study examines KSHV infection in B cells extracted from the tonsils of 40 human donors in order to determine what types of B cells are initially targeted for infection and examine how the presence (or absence) of other immune cells influence the initial stages of KSHV infection. We found that a variety of B cell subtypes derived from tonsils can be infected with KSHV. Interestingly, plasma cells (mature antibody-secreting B cells) were a highly targeted cell type. These results lay the foundation for further studies into the specific biology of KSHV in different types of B cells, an effort that may help us ultimately discover how to prevent the establishment of infection in these cells or reveal new ways to halt the progression of B cell cancers associated with KSHV infection.