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Abstract Herpes simplex virus type 1 (HSV‐1) is a human pathogen that causes recurrent infections. Acyclovir‐resistant strains exist and can cause severe complications, which are potentially untreatable with current therapies. We have developed siRNA swarms that target a 653 base pair long region of the essential HSV gene UL29. As per our previous results, the anti‐UL29 siRNA swarm effectively inhibits the replication of circulating HSV strains and acyclovir‐resistant HSV strains in vitro, while displaying a good safety profile. We investigated a single intranasal therapeutic dose of a siRNA swarm in mice, which were first inoculated intranasally with HSV‐1 and given treatment 4 h later. We utilized a luciferase‐expressing HSV‐1 strain, which enabled daily follow‐up of infection with in vivo imaging. Our results show that a single dose of a UL29‐targeted siRNA swarm can inhibit the replication of HSV‐1 in orofacial tissue, which was reflected in ex vivo HSV titers and HSV DNA copy numbers as well as by a decrease in a luciferase‐derived signal. Furthermore, the treatment had a tendency to protect mice from severe clinical symptoms and delay the onset of the symptoms. These results support the development of antiviral siRNA swarms as a novel treatment for HSV‐1 infections.

Herpes simplex virus type 1 (HSV-1) is the only FDA- and EMA- approved oncolytic virus, and accordingly, many potential oncolytic HSVs (oHSV) are in clinical development. The utilized oHSV parental strains are, however, mostly based on laboratory reference strains, which may possess a compromised cytolytic capacity in contrast to circulating strains of HSV-1. Here, we assess the phenotype of thirty-six circulating HSV-1 strains from Finland to uncover their potential as oHSV backbones. First, we determined their capacity for cell-to-cell versus extracellular spread, to find strains with replication profiles favorable for each application. Second, to unfold the differences, we studied the genetic diversity of two relevant viral glycoproteins (gB/UL27, gI/US7). Third, we examined the oncolytic potential of the strains in cells representing glioma, lymphoma, and colorectal adenocarcinoma. Our results suggest that the phenotype of a circulating isolate, including the oncolytic potential, is highly related to the host cell type. Nevertheless, we identified isolates with increased oncolytic potential in comparison with the reference viruses across many or all of the studied cancer cell types. Our research emphasizes the need for careful selection of the backbone virus in early vector design, and it highlights the potential of clinical isolates as backbones in oHSV development.