Blimp-1-Dependent Plasma Cell Differentiation Is Required for Efficient Maintenance of Murine Gammaherpesvirus Latency and Antiviral Antibody Responses

• Type of Material: Article
• Authors: Andrea M. Siegel, Emory University; Udaya Shankari Rangaswamy, Emory University; Ruth J. Napier, Emory University; Sam Speck, Emory University
• Language: English
• Date: 2010-01
• Publisher: American Society for Microbiology (ASM)
• Publication Version: Final Published Version
• Copyright Statement: © 2010, American Society for Microbiology
• Final Published Version (URL): http://jvi.asm.org/content/84/2/674
• Title of Journal or Parent Work: Journal of Virology
• Volume: 84
• Issue: 2
• Start Page: 674
• End Page: 685
• Grant/Funding Information: This research was supported by NIH grant R01 CA52004 to S.H.S., who was also supported by NIH grants R01 CA43143, CA58524, and AI58057.
• Research Categories: Biology, Virology

Abstract

Recent evidence from the study of Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus supports a model in which terminal differentiation of B cells to plasma cells leads to virus reactivation. Here we address the role of Blimp-1, the master transcriptional regulator of plasma cell differentiation, in murine gammaherpesvirus 68 (MHV68) latency and reactivation. Blimp-1 expression in infected cells was dispensable for acute virus replication in the lung following intranasal inoculation and in the spleen following intraperitoneal inoculation with MHV68. However, we observed a role for Blimp-1 in both the establishment of latency and reactivation from latency in vivo. Additionally, plasma cell-deficient mice also exhibited a significant defect in the establishment of latency in the spleen, as well as reactivation from latency, similar to mice that lacked Blimp-1 only in MHV68-infected cells. In the absence of plasma cells, MHV68 infection failed to elicit a strong germinal center response and fewer B cells in the germinal center were MHV68 infected. Notably, the absence of a functional Blimp-1 gene only in MHV68-infected cells led to a decrease in both B-cell and CD4+ T-cell responses during the establishment of latency. Finally, Blimp-1 expression in infected cells played a critical role in the maintenance of both MHV68 latency in the spleen and antibody responses to MHV68. Together, these studies support a model wherein episodic Blimp-1-mediated plasma cell differentiation leads to MHV68 reactivation, which serves to both renew the latency reservoirs and stimulate long-lived plasma cells to secrete virus-specific antibody.