Faculty Collaboration Database

B cell-intrinsic IRF-1 and conserved gammaherpesvirus protein kinase cooperate to promote murine gammaherpesvirus-driven germinal center response and splenic latent reservoir. J Virol 2025 Dec 23;99(12):e0137525

Date

11/20/2025

Pubmed ID

41263556

Pubmed Central ID

PMC12724244

DOI

10.1128/jvi.01375-25

Scopus ID

2-s2.0-105025661327 (requires institutional sign-in at Scopus site)

Abstract

Gammaherpesviruses infect >90% of adults and are associated with B cell lymphomas. These viruses drive the expansion and differentiation of germinal center B cells to amplify latent viral reservoir and ensure life-long infection of memory B cells. Additionally, infected germinal center B cells seed viral lymphomagenesis. We previously demonstrated that global deficiency of Interferon Regulatory Factor-1 (IRF-1), a classically antiviral transcription factor, results in increased murine gammaherpesvirus-driven germinal center response and latent viral reservoir. In contrast, B cell-specific loss of IRF-1 expression attenuates murine gammaherpesvirus chronic infection and germinal center response. All gammaherpesviruses encode a conserved protein kinase. We previously showed that the murine gammaherpesvirus protein kinase antagonizes the antiviral activity of global IRF-1 expression to support the establishment of chronic infection. Intriguingly, in this study, we show cooperation between the gammaherpesvirus protein kinase and B cell-intrinsic IRF-1 expression that supported optimal establishment of splenic latent viral reservoir and murine gammaherpesvirus-driven germinal center response. Both viral protein kinase and B cell-intrinsic IRF-1 expression supported the survival and proliferation of germinal center B cells during chronic gammaherpesvirus infection. Elevated DNA damage response or Fas/FasL expression was not observed, failing to account for elevated apoptosis of IRF-1-deficient germinal center B cells. However, B cell-intrinsic IRF-1 deficiency led to decreased MHC-II expression by germinal center B cells during chronic gammaherpesvirus infection. In summary, the results of this study illustrate the critical role of the cell type in defining the functional outcome of the host-viral interaction.IMPORTANCEGammaherpesviruses are highly prevalent pathogens that uniquely target B cells for the establishment of life-long infection. This study demonstrates cooperation between a conserved gammaherpesvirus protein kinase and B cell-intrinsic IRF-1, a classical host antiviral factor. We show that this cooperation is critical to support proliferation and survival of germinal center B cells, a subset of B cells that is latently infected by gammaherpesviruses and is critical for both the establishment of chronic infection and viral lymphomagenesis.

Author List

Rahlf CR, Jondle CN, Johansen ER, Tarakanova VL

Author

Vera Tarakanova PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
B-Lymphocytes
Gammaherpesvirinae
Germinal Center
Herpesviridae Infections
Interferon Regulatory Factor-1
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein Kinases
Spleen
Viral Proteins
Virus Latency