Background: Herpes simplex virus DNA synthesis requires seven interacting virus proteins.Results: Mapping revealed an N-terminal domain of UL52 primase interacting with UL5 helicase; a UL52 middle domain binds UL8 and the UL29 single strand DNA-binding protein.Conclusion: Protein-protein interactions in the helicase-primase were affected by an antiviral compound and resistance mutations.Significance: This work provides understanding of antiviral inhibition of replisome function.
Background:The herpes simplex virus replisome is composed of seven proteins encoded by the virus. Results: Analyses of hybrid replisomes revealed species-specific interactions, and mutagenesis of UL8 identified amino acids required for DNA synthesis and UL52 primase interaction.
Conclusion:The herpesvirus replisome is a conserved molecular machine with species-specific interactions. Significance: This work provides functional and mechanistic insights into herpesvirus replication.
We report a case of rapid eradication of melanoma brain metastases and simultaneous near-fatal encephalomyelitis following double immune checkpoint blockade. Brain damage marker S-100B and C reactive protein increased before symptoms or signs of encephalomyelitis and peaked when the patient fell into a coma. At that point, additional brain damage markers and peripheral T cell phenotype was analyzed. The analyses were repeated four times during the patient’s recovery. Axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and cerebrospinal fluid and gradually normalized after immunosuppression and intensive care. The costimulatory receptor inducible T cell costimulatory receptor (ICOS) was expressed on a high proportion of CD4+ and CD8+T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement. Both single and double immune checkpoint inhibitor-treated melanoma patients with other serious immune-related adverse events (irAE) (n=9) also expressed ICOS on a significantly higher proportion of CD4+ and CD8+T cells compared with controls without irAE (n=12). In conclusion, our results suggest a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damage markers in blood could facilitate early diagnosis of encephalitis.
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