Dataset Information

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

ABSTRACT: 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 UL29 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 (IC₅₀) 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 (IC₅₀ 1.0 nM; I_max 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.

SUBMITTER: Kalke K

PROVIDER: S-EPMC7764767 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Kalke Kiira K Lehtinen Jenni J Gnjatovic Jelena J Lund Liisa M LM Nyman Marie C MC Paavilainen Henrik H Orpana Julius J Lasanen Tuomas T Frejborg Fanny F Levanova Alesia A AA Vuorinen Tytti T Poranen Minna M MM Hukkanen Veijo V

Viruses 20201213 12

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 <i>UL29</i> essential ...[more]

PMID: 33322225

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Project description:Importance:The role of herpes simplex virus (HSV) reactivation on morbidity and mortality in patients in the intensive care unit requiring mechanical ventilation remains unknown. Objective:To determine whether preemptive treatment with intravenous acyclovir reduces the duration of mechanical ventilation in patients with HSV oropharyngeal reactivation. Design, Setting, and Participants:A double-blind, placebo-controlled randomized clinical trial was conducted in 16 intensive care units in France. Participants included 239 adults (age, >18 years) who received mechanical ventilation for at least 96 hours and continued to receive mechanical ventilation for 48 hours or more, with HSV oropharyngeal reactivation. Patients were enrolled between February 2, 2014, and February 22, 2018. Interventions:Participants were randomized to receive intravenous acyclovir, 5 mg/kg, 3 times daily for 14 days or a matching placebo. Main Outcomes and Measures:The primary end point was ventilator-free days from randomization to day 60. Prespecified secondary outcomes included mortality at 60 days. Main analyses were conducted on an intention-to-treat basis. Results:Of 239 patients enrolled and randomized, 1 patient withdrew consent, leaving 238 patients, with 119 patients in both the acyclovir and placebo (control) groups (median [IQR] age, 61 [50-70] years; 76 [32%] women) available for primary outcome measurement. On day 60, the median (IQR) numbers of ventilator-free days were 35 (0-53) for acyclovir recipients and 36 (0-50]) for controls (P?=?.17 for between-group comparison). Among secondary outcomes, 26 patients (22%) and 39 patients (33%) had died at day 60 (risk difference, 0.11, 95% CI, -0.004 to 0.22, P?=?.06). The adverse event frequency was similar for both groups (28% in the acyclovir group and 23% in the placebo group, P?=?.40), particularly acute renal failure post randomization affecting 3 acyclovir recipients (3%) and 2 controls (2%). Four patients (3%) in the acyclovir group vs none in the placebo group stopped the study drug for treatment-related adverse events. Conclusions and Relevance:In patients receiving mechanical ventilation for 96 hours or more with HSV reactivation in the throat, use of acyclovir, 5 mg/kg, 3 times daily for 14 days, did not increase the number of ventilator-free days at day 60, compared with placebo. These findings do not appear to support routine preemptive use of acyclovir in this setting. Trial Registration:ClinicalTrials.gov identifier: NCT02152358.

Dataset Information

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

Publications

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

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