Herpes Simplex Virus Type 1 Clinical Isolates Respond to UL29-Targeted siRNA Swarm Treatment Independent of Their Acyclovir Sensitivity
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 enzymatica...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/12/12/1434 |
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| author | Kiira Kalke Jenni Lehtinen Jelena Gnjatovic Liisa M. Lund Marie C. Nyman Henrik Paavilainen Julius Orpana Tuomas Lasanen Fanny Frejborg Alesia A. Levanova Tytti Vuorinen Minna M. Poranen Veijo Hukkanen |
| author_facet | Kiira Kalke Jenni Lehtinen Jelena Gnjatovic Liisa M. Lund Marie C. Nyman Henrik Paavilainen Julius Orpana Tuomas Lasanen Fanny Frejborg Alesia A. Levanova Tytti Vuorinen Minna M. Poranen Veijo Hukkanen |
| author_sort | Kiira Kalke |
| collection | DOAJ |
| description | 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 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<sub>50</sub>) 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<sub>50</sub> 1.0 nM; I<sub>max</sub> 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. |
| first_indexed | 2024-03-10T14:06:07Z |
| format | Article |
| id | doaj.art-a8340c0906c84b6299a226705499c641 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T14:06:07Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-a8340c0906c84b6299a226705499c6412023-11-21T00:38:36ZengMDPI AGViruses1999-49152020-12-011212143410.3390/v12121434Herpes Simplex Virus Type 1 Clinical Isolates Respond to UL29-Targeted siRNA Swarm Treatment Independent of Their Acyclovir SensitivityKiira Kalke0Jenni Lehtinen1Jelena Gnjatovic2Liisa M. Lund3Marie C. Nyman4Henrik Paavilainen5Julius Orpana6Tuomas Lasanen7Fanny Frejborg8Alesia A. Levanova9Tytti Vuorinen10Minna M. Poranen11Veijo Hukkanen12Institute of Biomedicine, University of Turku, 20520 Turku, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandMolecular and Integrative Biosciences Research Programme, Biological and Environmental Sciences, University of Helsinki, 00790 Helsinki, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandMolecular and Integrative Biosciences Research Programme, Biological and Environmental Sciences, University of Helsinki, 00790 Helsinki, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandAcyclovir 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 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<sub>50</sub>) 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<sub>50</sub> 1.0 nM; I<sub>max</sub> 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.https://www.mdpi.com/1999-4915/12/12/1434herpes simplex virusantiviralRNAisiRNAacycloviracyclovir resistance |
| spellingShingle | Kiira Kalke Jenni Lehtinen Jelena Gnjatovic Liisa M. Lund Marie C. Nyman Henrik Paavilainen Julius Orpana Tuomas Lasanen Fanny Frejborg Alesia A. Levanova Tytti Vuorinen Minna M. Poranen Veijo Hukkanen Herpes Simplex Virus Type 1 Clinical Isolates Respond to UL29-Targeted siRNA Swarm Treatment Independent of Their Acyclovir Sensitivity Viruses herpes simplex virus antiviral RNAi siRNA acyclovir acyclovir resistance |
| title | Herpes Simplex Virus Type 1 Clinical Isolates Respond to UL29-Targeted siRNA Swarm Treatment Independent of Their Acyclovir Sensitivity |
| title_full | Herpes Simplex Virus Type 1 Clinical Isolates Respond to UL29-Targeted siRNA Swarm Treatment Independent of Their Acyclovir Sensitivity |
| title_fullStr | Herpes Simplex Virus Type 1 Clinical Isolates Respond to UL29-Targeted siRNA Swarm Treatment Independent of Their Acyclovir Sensitivity |
| title_full_unstemmed | Herpes Simplex Virus Type 1 Clinical Isolates Respond to UL29-Targeted siRNA Swarm Treatment Independent of Their Acyclovir Sensitivity |
| title_short | Herpes Simplex Virus Type 1 Clinical Isolates Respond to UL29-Targeted siRNA Swarm Treatment Independent of Their Acyclovir Sensitivity |
| title_sort | herpes simplex virus type 1 clinical isolates respond to ul29 targeted sirna swarm treatment independent of their acyclovir sensitivity |
| topic | herpes simplex virus antiviral RNAi siRNA acyclovir acyclovir resistance |
| url | https://www.mdpi.com/1999-4915/12/12/1434 |
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