Gammaherpesvirus infection of myeloid cells reveals divergent outcomes regulated by host and viral factors

The gammaherpesviruses establish a lifelong infection, with the cellular outcome of infection intimately regulated by cell type. Myeloid cells are an early infection target characterized by diverse outcomes. To investigate this, we use murine gammaherpesvirus 68 to demonstrate that macrophages are readily infectable, resulting in three divergent infection outcomes dictated by viral and host factors. Infection in vivo and in a cell culture model results in a high frequency of viable cells characterized by restricted viral transcription and unexpected transcription of the ORF75 locus, with rare cells initiating lytic replication. Restricted infection can be fully converted to productive lytic replication by pre-treatment with the host cytokine interleukin 4 (IL-4). Finally, infection with a high viral dose also results in productive infection, but it triggers increased cell death. These studies demonstrate stepwise regulation of virus infection and identify virus and host factors that dictate divergent outcomes in a single cell type.