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Murid herpesvirus-4 (MuHV-4), Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus all infect B cells. Latent infection can spread by B cell recirculation and proliferation, but whether this alone achieves systemic infection is unclear. To test the need of MuHV-4 for lytic infection in B cells, we flanked its essential ORF50 lytic transactivator with\n            <jats:italic>loxP<\/jats:italic>\n            sites and then infected mice expressing B cell-specific Cre (CD19-Cre). The floxed virus replicated normally in Cre\n            <jats:sup>\u2212<\/jats:sup>\n            mice. In CD19-Cre mice, nasal and lymph node infections were maintained; but there was little splenomegaly, and splenic virus loads remained low. Cre-mediated removal of other essential lytic genes gave a similar phenotype. CD19-Cre spleen infection by intraperitoneal virus was also impaired. Therefore, MuHV-4 had to emerge lytically from B cells to colonize the spleen. An important role for B cell lytic infection in host colonization is consistent with the large CD8\n            <jats:sup>+<\/jats:sup>\n            T cell responses made to gammaherpesvirus lytic antigens during infectious mononucleosis and suggests that vaccine-induced immunity capable of suppressing B cell lytic infection might reduce long-term virus loads.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Gammaherpesviruses cause B cell cancers. Most models of host colonization derive from cell cultures with continuous, virus-driven B cell proliferation. However, vaccines based on these models have worked poorly. To test whether proliferating B cells suffice for host colonization, we inactivated the capacity of MuHV-4, a gammaherpesvirus of mice, to reemerge from B cells. The modified virus was able to colonize a first wave of B cells in lymph nodes but spread poorly to B cells in secondary sites such as the spleen. Consequently, viral loads remained low. These results were consistent with virus-driven B cell proliferation exploiting normal host pathways and thus having to transfer lytically to new B cells for new proliferation. We conclude that viral lytic infection is a potential target to reduce B cell proliferation.\n          <\/jats:p>","DOI":"10.1128\/jvi.02199-17","type":"journal-article","created":{"date-parts":[[2018,1,15]],"date-time":"2018-01-15T08:34:07Z","timestamp":1516005247000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["Gammaherpesvirus Colonization of the Spleen Requires Lytic Replication in B Cells"],"prefix":"10.1128","volume":"92","author":[{"given":"Clara","family":"Lawler","sequence":"first","affiliation":[{"name":"School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia"}]},{"given":"Marta Pires","family":"de Miranda","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal"}]},{"given":"Janet","family":"May","sequence":"additional","affiliation":[{"name":"Division of Virology, University of Cambridge, Cambridge, United Kingdom"}]},{"given":"Orry","family":"Wyer","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia"}]},{"given":"J. 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