Murine gammaherpesvirus infection is skewed toward Igλ+ B cells expressing a specific heavy chain V-segment.

One of the defining characteristics of the B cell receptor (BCR) is the extensive diversity in the repertoire of immunoglobulin genes that make up the BCR, resulting in broad range of specificity. Gammaherpesviruses are B lymphotropic viruses that establish life-long infection in B cells, and although the B cell receptor plays a central role in B cell biology, very little is known about the immunoglobulin repertoire of gammaherpesvirus infected cells. To begin to characterize the Ig genes expressed by murine gammaherpesvirus 68 (MHV68) infected cells, we utilized single cell sorting to sequence and clone the Ig variable regions of infected germinal center (GC) B cells and plasma cells. We show that MHV68 infection is biased towards cells that express the Ig lambda light chain along with a single heavy chain variable gene, IGHV10-1*01. This population arises through clonal expansion but is not viral antigen specific. Furthermore, we show that class-switching in MHV68 infected cells differs from that of uninfected cells. Fewer infected GC B cells are class-switched compared to uninfected GC B cells, while more infected plasma cells are class-switched compared to uninfected plasma cells. Additionally, although they are germinal center derived, the majority of class switched plasma cells display no somatic hypermutation regardless of infection status. Taken together, these data indicate that selection of infected B cells with a specific BCR, as well as virus mediated manipulation of class switching and somatic hypermutation, are critical aspects in establishing life-long gammaherpesvirus infection. Author summary Murine gammaherpesvirus 68 is a rodent pathogen that is closely related to the human gammaherpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated virus. All know gammaherpesviruses are associated with the development of lymphomas, as well as other cancers, in a small subset of infected individuals-particularly those with underlying defects in their immune system (i.e., transplant recipients and HIV infected patients). Because there are very limited small animal models for the human gammaherpesviruses, studies on murine gammaherepsviruses 68 can provide important insights into critical aspects of gammaherpesvirus infections and the association of these viruses with disease development. Another feature of all gammaherpesviruses is their ability to establish a chronic infection of their host-where the virus is maintained for the lifetime of the infected individual. The major target cell harboring chronic gammaherepsvirus infection are B lymphocytes-the cells in the immune system that produce antibodies in response to infections. Here we provide a detailed characterization of the populations of B lymphocytes that become infected by murine gammaherpesvirus 68. This has led to the identification of a specific population of B lymphocytes that is preferentially infected by the virus. This supports a model in which murine gammaherpesvirus infection of B lymphocytes is not random. However, it remains unclear why the virus targets this specific population of B cells for infection.