Herpes Simplex Virus Type 1 Clinical Isolates Respond to UL29-Targeted siRNA Swarm Treatment Independent of Their Acyclovir Sensitivity

• Published in: Viruses 2020-12, Vol.12 (12), p.1434
• Main Authors: Kalke, Kiira, Lehtinen, Jenni, Gnjatovic, Jelena, Lund, Liisa M, Nyman, Marie C, Paavilainen, Henrik, Orpana, Julius, Lasanen, Tuomas, Frejborg, Fanny, Levanova, Alesia A, Vuorinen, Tytti, Poranen, Minna M, Hukkanen, Veijo
• Format: Article
• Language: English
• Subjects: Acyclovir; Acyclovir - pharmacology; Acyclovir - therapeutic use; acyclovir resistance; Animals; antiviral; Antiviral agents; Antiviral drugs; Chlorocebus aethiops; Clinical isolates; DNA-Binding Proteins - genetics; Dose-Response Relationship, Drug; Drug Resistance, Viral - drug effects; Drug Resistance, Viral - genetics; Genes; Herpes simplex; Herpes Simplex - therapy; Herpes Simplex - virology; herpes simplex virus; Herpes viruses; Herpesvirus 1, Human - classification; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - isolation & purification; Humans; Infections; Inhibitory Concentration 50; RNA Interference; RNA, Small Interfering - genetics; RNA-mediated interference; RNAi; siRNA; Strains (organisms); Thymidine; Thymidine kinase; Vero Cells; Viral infections; Viral Proteins - genetics
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v12121434

Acyclovir is the drug of choice for the treatment of herpes simplex virus (HSV) infections. Acyclovir-resistant HSV strains may emerge, especially during long-term drug use, and subsequently cause difficult-to-treat exacerbations. Previously, we set up a novel treatment approach, based on enzymatically synthesized pools of siRNAs, or siRNA swarms. These swarms can cover kilobases-long target sequences, reducing the likelihood of resistance to treatment. Swarms targeting the essential gene of HSV-1 have demonstrated high efficacy against HSV-1 in vitro and in vivo. Here, we assessed the antiviral potential of a UL29 siRNA swarm against circulating strains of HSV-1, in comparison with acyclovir. All circulating strains were sensitive to both antivirals, with the half-maximal inhibitory concentrations (IC ) in the range of 350-1911 nM for acyclovir and 0.5-3 nM for the UL29 siRNA swarm. Additionally, we showed that an acyclovir-resistant HSV-1, devoid of thymidine kinase, is highly sensitive to UL29 siRNA treatment (IC 1.0 nM; I 97%). Moreover, the detected minor variations in the RNAi target of the HSV strains had no effect on the potency or efficacy of UL29 siRNA swarm treatment. Our findings support the development of siRNA swarms for the treatment of HSV-1 infections, in order to circumvent any potential acyclovir resistance.