Summary auto-generated
This study investigates genetic regions of herpes simplex virus (HSV) responsible for resistance to interferon (IFN). Researchers used two IFN-sensitive HSV strains—HSV-1(17syn) and HSV-2(UW268)—and found that co-infection led to complementation and production of IFN-resistant intertypic recombinants. Restriction enzyme analysis of these recombinants revealed that the BamHI-A, BglII-I, and BglII-N fragments were commonly lost, suggesting these regions contain IFN-resistance genes. Through marker rescue experiments, researchers cloned these fragments from an IFN-resistant HSV-2(G) strain and co-transfected them with the sensitive HSV-2(UW268) genome. Only the BglII-N fragment restored IFN resistance, increasing plating efficiency in IFN-treated cells. An IFN-resistant clone (HSV-2(C5001)) was isolated from this co-transfection, and sequencing confirmed recombination had occurred between the HSV-2(UW268) genome and the BglII-N fragment of HSV-2(G). The BglII-N fragment contains three open reading frames: UL40, UL41, and UL42. The authors conclude that the virion host shutoff (vhs) protein, encoded by UL41, is likely responsible for IFN resistance through its ability to degrade host mRNA and inhibit IFN-induced antiviral protein synthesis.
Key findings
- HSV IFN resistance is controlled by at least two distinct genetic regions
- The BglII-N fragment of HSV-2 contains a gene responsible for IFN resistance, distinct from previously identified regions
- The virion host shutoff (vhs) protein encoded by ORF UL41 is the most likely candidate for mediating IFN resistance through mRNA degradation
- Marker rescue experiments demonstrated that only the BglII-N fragment, not overlapping BamHI fragments, could restore IFN resistance to sensitive HSV strains
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Abstract
Double infection with two interferon (IFN)-sensitive strains of herpes simplex virus (HSV), HSV-1(17syn) and HSV-2(UW268), showed reduced inhibition of virus growth by IFN. Intertypic recombinants with IFN resistance were obtained from the doubly infected cultures. These results indicate that HSV IFN resistance is controlled by at least two genetic regions. Restriction endonuclease analysis demonstrated that the recombinants were similar to HSV-2 in their genomic structure but the BamHI-A, BglII-I and BglII-N fragments of HSV-2 were commonly lost in the recombinants, suggesting that any of these fragments could be associated with HSV-2 IFN resistance. We cloned these fragments and BamHI-E, which overlaps BglII-N, from an IFN-resistant HSV-2 strain, HSV-2(G), and examined each fragment for its ability to rescue IFN resistance of HSV-2(UW268) by co-transfecting with the HSV-2(UW268) genome. Of the HSV-2(G) fragments, only BglII-N increased plating efficiency of progeny viruses in IFN-treated cells. An IFN-resistant HSV-2 clone was obtained from the BglII-N of HSV-2(G) and HSV-2(UW268) genome co-transfected culture, and a part of BglII-N of HSV-2(UW268) was replaced with that of HSV-2(G) in the HSV-2 clone. Thus, it was concluded that one of the HSV regions encoding IFN resistance is located on the BglII-N fragment of HSV-2.