Virology in real hosts

Sindbis virus-infected neurons The interference of animal viruses with host translation was first documented in the 1960s in human fibroblasts infected with poliovirus. Further studies revealed that the halt of host translation (or “shut off”) was a general phenomenon observed in cells infected with lytic RNA and DNA viruses. Of the three steps in protein synthesis, viruses mainly affect the initiation step by hijacking or modifying the activity of key eukaryotic initiation factors (eIFs) to ensure an efficient translation of viral mRNAs and the simultaneous decline of host translation. The main targets of viruses are components of the cap-binding complex (eIF4F) that are required for the recruitment of ribosomes to mRNAs.

Infection of cultured cells with lytic animal viruses often results in “shut off”, but there is no direct or indirect evidence supporting the idea that it also should operate in whole animals infected with viruses. To address this issue, the authors of a new paper constructed a 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, this work demonstrates 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.

Inhibition of host translation by virus infection in vivo. PNAS USA May 10 2010 doi: 10.1073/pnas.100411010

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