3 years ago

Gamma-herpesvirus colonization of the spleen requires lytic replication in B cells.

Philip G Stevenson, Clara Lawler, J Pedro Simas, Orry Wyer, Marta Pires de Miranda, Janet May
Gamma-herpesviruses infect lymphocytes and cause lymphocytic cancers. Murid Herpesvirus-4 (MuHV-4), Epstein-Barr virus and the 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 loxP sites, then infected mice with B cell-specific cre expression (CD19-cre). The floxed virus replicated normally in cre- 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+ T cell responses made to gamma-herpesvirus lytic antigens during infectious mononucleosis, and suggests that vaccine-induced immunity capable of suppressing B cell lytic infection might reduce long-term virus loads.IMPORTANCE Gamma-herpesviruses 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 gamma-herpesvirus of mice, to re-emerge 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 so 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.

Publisher URL: http://doi.org/10.1128/JVI.02199-17

DOI: 10.1128/JVI.02199-17

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