Cells respond to environmental stress and proinflammatory cytokines by stimulating the Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase cascades. Infection of eukaryotic cells with herpes simplex virus type 1 (HSV-1) resulted in stimulation of both JNK/SAPK and p38 mitogen-activated protein kinase after 3 h of infection, and activation reached a maximum of 4-fold by 9 h post-infection. By using a series of mutant viruses, we showed that the virion transactivator protein VP16 stimulates p38/JNK, whereas no immediate-early, early, or late viral expressed gene is involved. We identified the stress-activated protein kinase kinase 1 as an upstream activator of p38/JNK, and we demonstrated that activation of AP-1 binding proceeded p38/JNK stimulation. During infection, the activated AP-1 consisted mainly of JunB and JunD with a simultaneous decrease in the cellular levels of Jun protein. We suggest that activation of the stress pathways by HSV-1 infection either represents a cascade triggered by the virus to facilitate the lytic cycle or a defense mechanism of the host cell against virus invasion.

SUMMARYImmediate-early (IE) mRNAs-4 and -5 of herpes simplex virus type 2 (HSV-2) are transcribed from the IRs/TRs genome regions towards the Us region. Each of these spliced mRNAs has an untranslated leader sequence of 249 bases and a single intron of approximately 540 bases which are contained entirely within TRs/IRs sequences. The DNA sequence of the intron largely comprises tandem reiterations of three distinct short sequences. Upstream of the common 5' mRNA termini the DNA sequence contains regions of homology with the equivalent region of HSV-1. Comparison of the polypeptides encoded by these HSV-2 mRNAs with those of HSV-1 shows blocks of conserved amino acids. The locations of the first initiator ATG triplets of these two HSV-2 mRNAs suggest that the IRs/TRs regions of HSV expand, by gene conversion or by equal though non-homologous crossover, to an extent determined by the functions of the DNA sequences which are duplicated or deleted as a result of the crossover. This mechanism for expansion of repeats may apply to other herpesviruses which have a genome structure similar to that of HSV.

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