Several different mechanisms are conceivable for the accumulation of phosphorylated eIF2a in rMP12-rLuc-infected in cells treated with ActD or a-amanitin (Figure 4 ). One possible mechanism relates to the eIF2a dephosphorylation step. Phosphorylation of eIF2a at Serine 51 induces a rapid synthesis of activating transcription factor (ATF)-4 mRNA, which can be translated in the presence of phosphorylated eIF2a [49] . Expressed ATF4 then induces GADD34 mRNA transcription [50] and GADD34 protein interacts with type 1 protein serine/ threonine phosphatase, PP1, and this complex dephosphorylates eIF2a to resume the cellular translation [51] . rMP12-rLuc replication in transcriptionally active cells probably induced PKR activation and eIF2a phosphorylation, the latter of which then induced GADD34 upregulation and subsequent eIF2a dephosphorylation allowing efficient viral translation. rMP12-rLuc replication in cells treated with ActD induced PKR activation, the extent of which was similar to that of infected, ActD-untreated cells ( Figure 6D ), whereas the transcription inhibitors would prevent GADD34 upregulation and subsequent eIF2a dephosphorylation, causing an accumulation of phosphorylated eIF2a, which inhibited viral translation. Other possible mechanisms relate to the failure to suppress the PKR function. Cells infected with adenovirus, human immunodeficiency virus-1, or herpes simplex virus undergo a dramatic increase in the abundance of Alu RNA, which carries a repetitive element of ,300-nt in length that is transcribed by RNA polymerase III [52, 53, 54, 55] . Alu RNA forms a stable complex with PKR, and antagonizes the PKR activation [56] . If rMP12-rLuc replication induces Alu RNA accumulation to prevent PKR activation, then the drug-induced transcriptional suppression would inhibit Alu RNA accumulation, preventing Alu RNA-mediated PKR inactivation. Another possibility is that rMP12-rLuc replication transcriptionally induces host mRNAs, and some of their gene products have PKR inhibition activities. An example of this possibility is that influenza virus replication induces P58 IPK , an inhibitor of PKR [57] . ActD or a-amanitin treatment suppresses the expression of the putative PKR inhibitor, resulting in an accumulation of phosphorylated eIF2a. Alternatively, transcriptional suppression may result in reduced amounts of ribosomal proteins, such as L18, which binds to PKR and inhibits PKR activation [58, 59] . These possibilities are not mutually exclusive, and the combination of these possibilities may contribute to the accumulation of phosphorylated eIF2a in the cells supporting replication of RVFV lacking the NSs in the presence of ActD or aamanitin.