ADAR1 Function Regulates Innate Immune Activation and Susceptibility to Viral Infections
Viral infection induces innate intracellular antiviral defenses, aimed at restricting virus replication and spread. Therefore, understanding the role and function of innate immune modulators can help to establish novel strategies for viral control. Here, we explore the role of ADAR1 as a regulator o...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-06-01
|
| Series: | Proceedings |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2504-3900/50/1/34 |
| _version_ | 1797565648652468224 |
|---|---|
| author | Maria Pujantell Eva Riveira-Muñoz Edurne García-Vidal Lucía Gutiérrez-Chamorro Roger Badia Bonaventura Clotet Ester Ballana |
| author_facet | Maria Pujantell Eva Riveira-Muñoz Edurne García-Vidal Lucía Gutiérrez-Chamorro Roger Badia Bonaventura Clotet Ester Ballana |
| author_sort | Maria Pujantell |
| collection | DOAJ |
| description | Viral infection induces innate intracellular antiviral defenses, aimed at restricting virus replication and spread. Therefore, understanding the role and function of innate immune modulators can help to establish novel strategies for viral control. Here, we explore the role of ADAR1 as a regulator of the HIV, HCV, and HPV infections, both in vitro and in vivo, in a genetic association study. Depletion of <i>ADAR1</i> induced innate immune activation, observed by a significant increase in <i>IFNB1</i> mRNA and CXCL10 expression. Further characterization of <i>ADAR1</i> knockdown also showed upregulation of the RNA sensors MDA5 and RIG-I, increased IRF7 expression, and phosphorylation of STAT1. ADAR1 deficiency had differential effects depending on the virus tested: siADAR1 cells showed a significant reduction in HIV-1 infection, whereas <i>ADAR1</i> knockdown suggested a proviral role in HCV and HPV infections. In addition, genetic association studies were performed in a cohort of 155 HCV/HIV individuals with chronic coinfection, and a cohort of 173 HPV/HIV-infected individuals was followed for a median of six years (range 0.1–24). Polymorphisms within the <i>ADAR1</i> gene were found to be significantly associated with poor clinical outcome of HCV therapy and advanced liver fibrosis in a cohort of HCV/HIV-1-coinfected patients. Moreover, we identified the low-frequency haplotype AACCAT to be significantly associated with recurrent HPV dysplasia, suggesting a role for ADAR1 in the outcome of HPV infection in HIV+ individuals. In conclusion, we show that ADAR1 regulates innate immune activation and plays a key role in susceptibility to viral infections by either limiting or enhancing viral replication. Overall, ADAR1 could be a potential target for designing immune-modulating therapeutic strategies. |
| first_indexed | 2024-03-10T19:16:05Z |
| format | Article |
| id | doaj.art-78a4df2d543245b78c3e3a4f3ba84030 |
| institution | Directory Open Access Journal |
| issn | 2504-3900 |
| language | English |
| last_indexed | 2024-03-10T19:16:05Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Proceedings |
| spelling | doaj.art-78a4df2d543245b78c3e3a4f3ba840302023-11-20T03:22:58ZengMDPI AGProceedings2504-39002020-06-015013410.3390/proceedings2020050034ADAR1 Function Regulates Innate Immune Activation and Susceptibility to Viral InfectionsMaria Pujantell0Eva Riveira-Muñoz1Edurne García-Vidal2Lucía Gutiérrez-Chamorro3Roger Badia4Bonaventura Clotet5Ester Ballana6AIDS Research Institute (IrsiCaixa), Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, SpainAIDS Research Institute (IrsiCaixa), Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, SpainAIDS Research Institute (IrsiCaixa), Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, SpainAIDS Research Institute (IrsiCaixa), Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, SpainAIDS Research Institute (IrsiCaixa), Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, SpainAIDS Research Institute (IrsiCaixa), Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, SpainAIDS Research Institute (IrsiCaixa), Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, SpainViral infection induces innate intracellular antiviral defenses, aimed at restricting virus replication and spread. Therefore, understanding the role and function of innate immune modulators can help to establish novel strategies for viral control. Here, we explore the role of ADAR1 as a regulator of the HIV, HCV, and HPV infections, both in vitro and in vivo, in a genetic association study. Depletion of <i>ADAR1</i> induced innate immune activation, observed by a significant increase in <i>IFNB1</i> mRNA and CXCL10 expression. Further characterization of <i>ADAR1</i> knockdown also showed upregulation of the RNA sensors MDA5 and RIG-I, increased IRF7 expression, and phosphorylation of STAT1. ADAR1 deficiency had differential effects depending on the virus tested: siADAR1 cells showed a significant reduction in HIV-1 infection, whereas <i>ADAR1</i> knockdown suggested a proviral role in HCV and HPV infections. In addition, genetic association studies were performed in a cohort of 155 HCV/HIV individuals with chronic coinfection, and a cohort of 173 HPV/HIV-infected individuals was followed for a median of six years (range 0.1–24). Polymorphisms within the <i>ADAR1</i> gene were found to be significantly associated with poor clinical outcome of HCV therapy and advanced liver fibrosis in a cohort of HCV/HIV-1-coinfected patients. Moreover, we identified the low-frequency haplotype AACCAT to be significantly associated with recurrent HPV dysplasia, suggesting a role for ADAR1 in the outcome of HPV infection in HIV+ individuals. In conclusion, we show that ADAR1 regulates innate immune activation and plays a key role in susceptibility to viral infections by either limiting or enhancing viral replication. Overall, ADAR1 could be a potential target for designing immune-modulating therapeutic strategies.https://www.mdpi.com/2504-3900/50/1/34ADAR1innate immunityIFNHIVHPVHCV |
| spellingShingle | Maria Pujantell Eva Riveira-Muñoz Edurne García-Vidal Lucía Gutiérrez-Chamorro Roger Badia Bonaventura Clotet Ester Ballana ADAR1 Function Regulates Innate Immune Activation and Susceptibility to Viral Infections Proceedings ADAR1 innate immunity IFN HIV HPV HCV |
| title | ADAR1 Function Regulates Innate Immune Activation and Susceptibility to Viral Infections |
| title_full | ADAR1 Function Regulates Innate Immune Activation and Susceptibility to Viral Infections |
| title_fullStr | ADAR1 Function Regulates Innate Immune Activation and Susceptibility to Viral Infections |
| title_full_unstemmed | ADAR1 Function Regulates Innate Immune Activation and Susceptibility to Viral Infections |
| title_short | ADAR1 Function Regulates Innate Immune Activation and Susceptibility to Viral Infections |
| title_sort | adar1 function regulates innate immune activation and susceptibility to viral infections |
| topic | ADAR1 innate immunity IFN HIV HPV HCV |
| url | https://www.mdpi.com/2504-3900/50/1/34 |
| work_keys_str_mv | AT mariapujantell adar1functionregulatesinnateimmuneactivationandsusceptibilitytoviralinfections AT evariveiramunoz adar1functionregulatesinnateimmuneactivationandsusceptibilitytoviralinfections AT edurnegarciavidal adar1functionregulatesinnateimmuneactivationandsusceptibilitytoviralinfections AT luciagutierrezchamorro adar1functionregulatesinnateimmuneactivationandsusceptibilitytoviralinfections AT rogerbadia adar1functionregulatesinnateimmuneactivationandsusceptibilitytoviralinfections AT bonaventuraclotet adar1functionregulatesinnateimmuneactivationandsusceptibilitytoviralinfections AT esterballana adar1functionregulatesinnateimmuneactivationandsusceptibilitytoviralinfections |