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SUMMARYSynthesis of cellular protein was substantially inhibited within I h of infection with herpes simplex virus, type 2, strain G (HSV-2). The inhibition also occurred, although no virus-specific protein synthesis was detected, after infection with u.v. irradiated virus and in cytoplasts that had been enucleated before infection. The inhibitory activity could not be distinguished from infectivity by dilution, sedimentation or reaction with y-globulin. HSV-2 also suppressed the synthesis of Sendal virus proteins, but not those specified by HSV-I.Host protein synthesis was no more sensitive than virus protein synthesis to an increased concentration of NaCI in the medium, nor could the suppression of host synthesis be prevented by adding excess MgC12 to the medium or by omitting CaC12 or NaCI. It was accompanied by the breakdown of polyribosomes, which also occurred in the presence of cycloheximide but not at 4 °C. The breakdown yielded ribosomes that were sensitive to a high salt concentration, unlike those produced by treatment of polyribosomes with RNase. The synthesis of cellular DNA and RNA was also inhibited following infection with u.v.-inactivated virus.It is concluded that the suppression of host protein synthesis (and probably also of host DNA and RNA synthesis) is caused by a constituent of the infecting virus particles. The mechanism is obscure but probably does not depend on the leakage out of the cell of Mg ~+ or into the cell of Ca 2+ or Na + ions, nor on the specific inhibition of initiation of host polypeptide chains, nor on RNase-like attack on host polyribosomes.

Gene UL41 of herpes simplex virus type 1 (HSV-1) and the corresponding gene of HSV-2, which control the virion-mediated early suppression of cellular protein synthesis, have been inactivated by inserting a flgalactosidase expression cassette into their coding regions. The resulting recombinants grew well in tissue culture, although with the type 2 recombinant viral protein synthesis was slightly delayed. As a result of inactivation of UL41 host protein synthesis was not suppressed in the presence of actinomycin or early in normal infection, although it declined at a late stage. Polyribosomes were not broken down early in infection, cellular DNA synthesis was not inhibited and in the presence of cycloheximide stable alpha (immediate early) mRNA accumulated, in marked contrast to that of the parent HSV-2 strain. Comparison of the proteins of purified virions of HSV-1 and shutoff-defective recombinant virus revealed discrepancies consistent with the presence of the UL41 gene product in the enveloped virion.

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SI~IMMARYThe ~ or immediate early mRNA of herpes simplex virus strain HSV-2(G) had a half-life of about 15 min if made in the absence of viral protein synthesis but was relatively stable if viral protein synthesis occurred, either freely or restricted by the presence of the proline analogue azetidine. In contrast, the ~ mRNA of other strains of the virus is stable, even in the absence of protein synthesis. Studies with recombinant viruses showed that the region of the viral DNA between 0.58 and 0.65 map units [which includes the gene (vhs, UL41) that controls virion-mediated shutoff of host protein synthesis] is important in determining the survival of ~ mRNA. In mixed infection experiments HSV-2(G) inhibited ~ as well as host protein synthesis but the shutoff activity appeared to be short-lived. Within 3 h after infection, as a result of protein synthesis, cells became completely resistant to shutoff by superinfecting virus.