Inhibition of host translation by virus infection in vivo

Infection of cultured cells with lytic animal viruses often results in the selective inhibition of host protein synthesis, whereas viral mRNA is efficiently translated under these circumstances. This phenomenon, known as shut off, has been well described at the molecular level for some viruses, but there is not yet any direct or indirect evidence supporting the idea that it also should operate in animals infected with viruses. To address this issue, we constructed recombinant Sindbis virus (SV)-expressing reporter mRNA, the translation of which is sensitive or resistant to virus-induced shut off. As found in cultured cells, replication of SV in mouse brain was associated with a strong phosphorylation of eukaryotic initiation factor (eIF2) that prevented translation of reporter mRNA(luciferase and EGFP). Translation of these reporters was restored in vitro, in vivo, and ex vivo when a viral RNA structure, termed downstream hairpin loop, present in viral 26S mRNA, was placed at the 5' end of reporter mRNAs. By comparing the expression of shut off-sensitive and -resistant reporters, we unequivocally concluded that replication of SV in animal tissues is associated with a profound inhibition of nonviral mRNA translation. A strategy as simple as that followed here might be applicable to other viruses to evaluate their interference on host translation in infected animals.