Summary auto-generated
This study demonstrates that the UL41 gene of herpes simplex virus types 1 and 2, which encodes the virion-associated host shutoff function, can be inactivated by inserting a β-galactosidase expression cassette into its coding region. The resulting recombinant viruses (17(41-) and G(41-)) grew viable in tissue culture, though G(41-) showed slightly delayed viral protein synthesis. Inactivation of UL41 eliminated the virus's ability to suppress host protein synthesis early in infection and prevented polyribosome breakdown and inhibition of cellular DNA synthesis. In the absence of functional UL41, alpha (immediate-early) mRNAs remained stable even in the presence of cycloheximide, contrasting sharply with wild-type virus. Virion protein analysis revealed differences consistent with the UL41 gene product being carried within enveloped virions. The findings establish that UL41 is not an essential structural component but is responsible for initiating both polysome disaggregation and cellular mRNA degradation, likely through activation of a nuclease. The results provide clear evidence for UL41's multifunctional role in viral shutoff mechanisms and suggest that viral gene products produced early in infection may protect viral mRNAs from UL41-mediated degradation.
Key findings
- UL41 gene inactivation in HSV-1 and HSV-2 produces viable virus, indicating UL41 protein is not essential for virion structure
- UL41 mutant viruses fail to suppress host protein synthesis, prevent polyribosome breakdown, and do not inhibit cellular DNA synthesis
- Without functional UL41, alpha mRNAs remain stable in the presence of cycloheximide, demonstrating UL41's role in mRNA degradation
- UL41 gene product is carried in enveloped virions as evidenced by protein composition differences between wild-type and mutant particles
- A virus-induced early protein likely protects viral mRNAs from UL41-mediated degradation during normal infection
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Abstract
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 -galactosidase 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.