Mechanisms of Establishment and Maintenance of RNA Virus Persistence in Primary Lymphocytes: a Dissertation

RNA virus persistence in lymphocytes has been studied extensively in vitro but the influence of lymphocyte homeostatic mechanisms and antiviral immunity on persistence has not been well studied in an in vivo system. It is demonstrated here that vesicular stomatitis virus (VSV), a negative-strand RNA virus , is maintained in B lymphocytes in vivo despite the existence of homeostatic mechanisms that drive the cells to proliferate under conditions of B cell deficiency and a strong antibody response to the virus. It is also shown that antiviral antibodies inhibit VSV reactivation from persistently infected primary B cells in vitro. A model is proposed for virus persistence in vivo which B cell homeostatic signals drve virus expression in some infected cells , resulting in an antibody response , which maintains virus persistence in B cells. In the course of conducting experiments to define the homeostatic signals that might act on persistently infected B cells in vivo it was found that a fraction of small resting splenic B cells proliferates after adoptive transfer into B cell deficient hosts (sublethally irradiated xid or SCID). This process, termed homeostatic proliferation , is driven by B cell deficiency since proliferation is limited in B cell sufficient hosts. This reveals the existence of a mechanism by which B cells sense their own numbers. The proliferation is unique in that the replicating cells do not upregulate cell surface markers, such as CD25 and B7, associated with antigen or mitogen induced proliferation. They , however, show transient increases in other activation markers (CD69 , CD71), demonstrating the action of an inductive signal. Homeostatic proliferation is a property of both mature and immature B cells , but in competition experiments, only mature B cells