As obligate intracellular parasites, viruses must ensure that their mRNAs efficiently engage the cellular translational apparatus. Indeed, studies of translational control during infection have revealed numerous strategies viruses use to subdue the cell, while ensuring high-level viral protein production. Nevertheless, our understanding of how dsDNA viruses manipulate the host translational machinery remains rudimentary. Here, I use Herpesvirus and Poxvirus models to explore mechanisms that control translation during reactivation of latent infections and in acute infection of primary cells.

To investigate how cellular translation pathways contribute to reactivation of latent viral infections, I utilized a B-cell line latently infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Inducing lytic reactivation dramatically suppressed ongoing protein synthesis and correlated with inactivation of the translational repressor 4E-BP1, nuclear PABP accumulation, and eIF4F complex assembly. In addition, virus reactivation induced eIF4E phosphorylation by the eIF4G-associated kinase Mnk, whose activity was critical for expression of the viral-transactivator Rta and efficient lytic reactivation. My observations establish that KSHV reactivation induces the remodeling and activation of the host translation initiation machinery, and highlight the importance of Mnk during viral emergence from latency.

Unlike reactivation from latency, acute infection requires de novo lytic infection in naïve cells. Vaccinia virus (VACV) was selected to study translational control in acutely infected cells in part because it encodes its own transcription and DNA synthesis machinery, but remains fully reliant on cellular translation functions. Here, I establish that acute infection of growth-arrested primary human cells with VACV results in the inactivation and destruction of 4E-BP1, enhanced eIF4F assembly and redistribution of eIF4E and eIF4G into cytoplasmic foci that correspond to viral replication compartments. Moreover, Mnk1 activation upon infection promotes eIF4E phosphorylation, viral protein accumulation and VACV replication. These effects are partially independent of Mnk1 kinase activity, suggesting that a novel kinase-independent Mnk1 function might contribute to viral protein synthesis.

Together, these observations define how the assembly and activity of the multi-subunit cellular translation initiation factor eIF4F are effectively manipulated during acute infection and reactivation from latency by two very different DNA viruses, using conserved and unique strategies.