Intrinsic p53 activation restricts gammaherpesvirus driven germinal center B cell expansion during latency establishment

Shana M. Owens, Jeffrey M. Sifford, Gang Li, Steven J. Murdock, Eduardo Salinas, Darby Oldenburg, Debopam Ghosh, Jason S. Stumhofer, Intawat Nookaew, Mark Manzano and J. Craig Forrest ()
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Shana M. Owens: University of Arkansas for Medical Sciences
Jeffrey M. Sifford: University of Arkansas for Medical Sciences
Gang Li: University of Arkansas for Medical Sciences
Steven J. Murdock: University of Arkansas for Medical Sciences
Eduardo Salinas: University of Arkansas for Medical Sciences
Darby Oldenburg: Gunderson Research Institute
Debopam Ghosh: University of Arkansas for Medical Sciences
Jason S. Stumhofer: University of Arkansas for Medical Sciences
Intawat Nookaew: University of Arkansas for Medical Sciences
Mark Manzano: University of Arkansas for Medical Sciences
J. Craig Forrest: University of Arkansas for Medical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Gammaherpesviruses are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus and murine gammaherpesvirus 68, this is accomplished through a viral gene-expression program that promotes cellular proliferation and differentiation, especially of germinal center B cells. Intrinsic host mechanisms that control virus-driven cellular expansion are incompletely defined. Using a small-animal model of gammaherpesvirus pathogenesis, we demonstrate in vivo that the tumor suppressor p53 is activated specifically in B cells latently infected by murine gammaherpesvirus 68. In the absence of p53, the early expansion of murine gammaherpesvirus 68 latency greatly increases, especially in germinal center B cells, a cell type whose proliferation is conversely restricted by p53. We identify the B cell-specific latency gene M2, a viral promoter of germinal center B cell differentiation, as a viral protein sufficient to elicit a p53-dependent anti-proliferative response caused by Src-family kinase activation. We further demonstrate that Epstein-Barr virus-encoded latent membrane protein 1 similarly triggers a p53 response in primary B cells. Our data highlight a model in which gammaherpesvirus latency gene-expression programs that promote B cell proliferation and differentiation to facilitate viral colonization of the host trigger aberrant cellular proliferation that is controlled by p53.

Date: 2025
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DOI: 10.1038/s41467-025-56247-5

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