Antiviral Evaluation of UV-4B and Interferon-Alpha Combination Regimens against Dengue Virus
Dengue virus (DENV) is a flavivirus associated with clinical manifestations ranging in severity from self-limiting dengue fever, to the potentially life threatening condition, severe dengue. There are currently no approved antiviral therapies for the treatment of DENV. Here, we evaluated the antivir...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-04-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/13/5/771 |
| _version_ | 1797536118150791168 |
|---|---|
| author | Evelyn J. Franco Camilly P. Pires de Mello Ashley N. Brown |
| author_facet | Evelyn J. Franco Camilly P. Pires de Mello Ashley N. Brown |
| author_sort | Evelyn J. Franco |
| collection | DOAJ |
| description | Dengue virus (DENV) is a flavivirus associated with clinical manifestations ranging in severity from self-limiting dengue fever, to the potentially life threatening condition, severe dengue. There are currently no approved antiviral therapies for the treatment of DENV. Here, we evaluated the antiviral potential of four broad-spectrum antivirals, UV-4B, interferon-alpha (IFN), sofosbuvir (SOF), and favipiravir (FAV) against DENV serotype 2 as mono- and combination therapy in cell lines that are physiologically relevant to human infection. Cell lines derived from human liver (HUH-7), neurons (SK-N-MC), and skin (HFF-1) were infected with DENV and treated with UV-4B, IFN, SOF, or FAV. Viral supernatant was sampled daily and infectious viral burden was quantified by plaque assay on Vero cells. Drug effect on cell proliferation in uninfected and infected cells was also assessed. UV-4B inhibited DENV in HUH-7, SK-N-MC, and HFF-1 cells yielding EC<sub>50</sub> values of 23.75, 49.44, and 37.38 µM, respectively. Clinically achievable IFN concentrations substantially reduced viral burden in HUH-7 (EC<sub>50</sub> = 102.7 IU/mL), SK-N-MC (EC<sub>50</sub> = 86.59 IU/mL), and HFF-1 (EC<sub>50</sub> = 163.1 IU/mL) cells. SOF potently inhibited DENV in HUH-7 cells but failed to produce the same effect in SK-N-MC and HFF-1 cells. Finally, FAV provided minimal suppression in HUH-7 and SK-N-MC cells, but was ineffective in HFF-1 cells. The two most potent anti-DENV agents, UV-4B and IFN, were also assessed in combination. UV-4B + IFN treatment enhanced antiviral activity in HUH-7, SK-N-MC, and HFF-1 cells relative to monotherapy. Our results demonstrate the antiviral potential of UV-4B and IFN against DENV in multiple physiologically relevant cell types. |
| first_indexed | 2024-03-10T11:55:06Z |
| format | Article |
| id | doaj.art-79be2d47a6124270b23273c0c4d37860 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T11:55:06Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-79be2d47a6124270b23273c0c4d378602023-11-21T17:23:33ZengMDPI AGViruses1999-49152021-04-0113577110.3390/v13050771Antiviral Evaluation of UV-4B and Interferon-Alpha Combination Regimens against Dengue VirusEvelyn J. Franco0Camilly P. Pires de Mello1Ashley N. Brown2Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, FL 32827, USAInstitute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, FL 32827, USAInstitute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, FL 32827, USADengue virus (DENV) is a flavivirus associated with clinical manifestations ranging in severity from self-limiting dengue fever, to the potentially life threatening condition, severe dengue. There are currently no approved antiviral therapies for the treatment of DENV. Here, we evaluated the antiviral potential of four broad-spectrum antivirals, UV-4B, interferon-alpha (IFN), sofosbuvir (SOF), and favipiravir (FAV) against DENV serotype 2 as mono- and combination therapy in cell lines that are physiologically relevant to human infection. Cell lines derived from human liver (HUH-7), neurons (SK-N-MC), and skin (HFF-1) were infected with DENV and treated with UV-4B, IFN, SOF, or FAV. Viral supernatant was sampled daily and infectious viral burden was quantified by plaque assay on Vero cells. Drug effect on cell proliferation in uninfected and infected cells was also assessed. UV-4B inhibited DENV in HUH-7, SK-N-MC, and HFF-1 cells yielding EC<sub>50</sub> values of 23.75, 49.44, and 37.38 µM, respectively. Clinically achievable IFN concentrations substantially reduced viral burden in HUH-7 (EC<sub>50</sub> = 102.7 IU/mL), SK-N-MC (EC<sub>50</sub> = 86.59 IU/mL), and HFF-1 (EC<sub>50</sub> = 163.1 IU/mL) cells. SOF potently inhibited DENV in HUH-7 cells but failed to produce the same effect in SK-N-MC and HFF-1 cells. Finally, FAV provided minimal suppression in HUH-7 and SK-N-MC cells, but was ineffective in HFF-1 cells. The two most potent anti-DENV agents, UV-4B and IFN, were also assessed in combination. UV-4B + IFN treatment enhanced antiviral activity in HUH-7, SK-N-MC, and HFF-1 cells relative to monotherapy. Our results demonstrate the antiviral potential of UV-4B and IFN against DENV in multiple physiologically relevant cell types.https://www.mdpi.com/1999-4915/13/5/771DENVantiviralfavipiravirsofosbuvirinterferonUV-4B |
| spellingShingle | Evelyn J. Franco Camilly P. Pires de Mello Ashley N. Brown Antiviral Evaluation of UV-4B and Interferon-Alpha Combination Regimens against Dengue Virus Viruses DENV antiviral favipiravir sofosbuvir interferon UV-4B |
| title | Antiviral Evaluation of UV-4B and Interferon-Alpha Combination Regimens against Dengue Virus |
| title_full | Antiviral Evaluation of UV-4B and Interferon-Alpha Combination Regimens against Dengue Virus |
| title_fullStr | Antiviral Evaluation of UV-4B and Interferon-Alpha Combination Regimens against Dengue Virus |
| title_full_unstemmed | Antiviral Evaluation of UV-4B and Interferon-Alpha Combination Regimens against Dengue Virus |
| title_short | Antiviral Evaluation of UV-4B and Interferon-Alpha Combination Regimens against Dengue Virus |
| title_sort | antiviral evaluation of uv 4b and interferon alpha combination regimens against dengue virus |
| topic | DENV antiviral favipiravir sofosbuvir interferon UV-4B |
| url | https://www.mdpi.com/1999-4915/13/5/771 |
| work_keys_str_mv | AT evelynjfranco antiviralevaluationofuv4bandinterferonalphacombinationregimensagainstdenguevirus AT camillyppiresdemello antiviralevaluationofuv4bandinterferonalphacombinationregimensagainstdenguevirus AT ashleynbrown antiviralevaluationofuv4bandinterferonalphacombinationregimensagainstdenguevirus |