Interference with Cellular Gene Expression

This chapter focuses on new advances in understanding viral inhibition of host gene expression at four levels: transcription, nucleocytoplasmic trafficking, translation initiation, and manipulation of mRNA granules that store or process mRNA. Blockage of host gene expression serves multiple functions of liberating ribonucleotides, charged amino- acyl tRNAs, and ribosomal machinery for viral use and also restricting expression of innate immune response polypeptides that could counter viral replication. Further, blockage of host gene expression can hamper premature cell apoptosis and promote cell lysis after viral assembly. Recently, viral interference with RNA metabolism has been shown to extend to spliceosome assembly. Interestingly, in contrast to enteroviruses, cardioviruses appear to inhibit mRNA export, and this difference may be due to the different mechanisms utilized by these viruses to inhibit nuclear transport. In addition to the cleavages of eIF4G and PABP, which have major functional consequences, picornavirus infection leads to the proteolytic processing of other accessory translation factors that likely contribute to host cell translation shutoff. Mechanistically, various cellular stresses, such as oxidative stress, heat shock, or nutrient deprivation, induce SG formation by driving phosphorylation of eIF2α, which causes generalized translational arrest, and accumulation of mRNPs with stalled 40S ribosome subunits in stress granules (SGs). In the future, a more complete understanding of the mechanisms by which these fascinating viruses manipulate host gene expression and linkage to specific pathologies could lead to the rational design of novel antiviral drugs and therapies to combat these viruses and limit or interrupt disease progression.