Targeted mutations in IFNα2 improve its antiviral activity against various viruses
ABSTRACTDuring viral infections, type I interferons (IFN) are induced and play a key role in counteracting initial viral spread. Twelve different human IFNα subtypes exist that bind the same receptor; however, they elicit unique host responses and display distinct potencies of antiviral activities....
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2023-12-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02357-23 |
| _version_ | 1797378870448488448 |
|---|---|
| author | Zehra Karakoese Vu-Thuy Khanh Le-Trilling Jonas Schuhenn Sandra Francois Mengji Lu Jia Liu Mirko Trilling Daniel Hoffmann Ulf Dittmer Kathrin Sutter |
| author_facet | Zehra Karakoese Vu-Thuy Khanh Le-Trilling Jonas Schuhenn Sandra Francois Mengji Lu Jia Liu Mirko Trilling Daniel Hoffmann Ulf Dittmer Kathrin Sutter |
| author_sort | Zehra Karakoese |
| collection | DOAJ |
| description | ABSTRACTDuring viral infections, type I interferons (IFN) are induced and play a key role in counteracting initial viral spread. Twelve different human IFNα subtypes exist that bind the same receptor; however, they elicit unique host responses and display distinct potencies of antiviral activities. Our previous studies on human immunodeficiency virus (HIV) and hepatitis B virus (HBV) demonstrated that the clinically used IFNα2 is not the most effective one among the IFNα subtypes. By sequence modeling, we identified a region in helix B with mainly conserved residues at the outside facing IFNAR1, but variable residues at the inside facing the core of IFNα, potentially representing a putative tunable anchor to tune pleiotropic IFN responses. Using site-directed mutagenesis, various mutations were introduced into the IFNα2b backbone targeting sites which are important for binding to IFNAR1 and IFNAR2, the putative tunable anchor, or outside these three regions. Selected mutations were based on sequence differences to high antiviral subtypes IFNα6 and IFNα14. Treatment assays against HBV and HIV identified several critical residues for the antiviral activity of IFNα mainly in the IFNAR1 binding region. Combined mutations of the IFNα2 IFNAR1/2 binding sites or the IFNAR1 binding region plus the putative tunable anchor by those of IFNα14 further augmented activation of different downstream signaling cascades providing a molecular correlate for the enhanced antiviral activity. We describe here important functional residues within IFNα subtype molecules, which enabled us to design novel and innovative drugs that may have the potential to be used in clinical trials against a variety of different viral infections.IMPORTANCEThe potency of interferon (IFN)α to restrict viruses was already discovered in 1957. However, until today, only IFNα2 out of the 12 distinct human IFNα subtypes has been therapeutically used against chronic viral infections. There is convincing evidence that other IFNα subtypes are far more efficient than IFNα2 against many viruses. In order to identify critical antiviral residues within the IFNα subtype sequence, we designed hybrid molecules based on the IFNα2 backbone with individual sequence motifs from the more potent subtypes IFNα6 and IFNα14. In different antiviral assays with HIV or HBV, residues binding to IFNAR1 as well as combinations of residues in the IFNAR1 binding region, the putative tunable anchor, and residues outside these regions were identified to be crucial for the antiviral activity of IFNα. Thus, we designed artificial IFNα molecules, based on the clinically approved IFNα2 backbone, but with highly improved antiviral activity against several viruses. |
| first_indexed | 2024-03-08T20:13:53Z |
| format | Article |
| id | doaj.art-377a20afbe4547f6abdae03324ad4c6a |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-03-08T20:13:53Z |
| publishDate | 2023-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-377a20afbe4547f6abdae03324ad4c6a2023-12-22T19:53:43ZengAmerican Society for MicrobiologymBio2150-75112023-12-0114610.1128/mbio.02357-23Targeted mutations in IFNα2 improve its antiviral activity against various virusesZehra Karakoese0Vu-Thuy Khanh Le-Trilling1Jonas Schuhenn2Sandra Francois3Mengji Lu4Jia Liu5Mirko Trilling6Daniel Hoffmann7Ulf Dittmer8Kathrin Sutter9University Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, GermanyUniversity Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, GermanyUniversity Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, GermanyUniversity Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, GermanyUniversity Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, GermanyJoint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, ChinaUniversity Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, GermanyJoint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, ChinaUniversity Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, GermanyUniversity Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, GermanyABSTRACTDuring viral infections, type I interferons (IFN) are induced and play a key role in counteracting initial viral spread. Twelve different human IFNα subtypes exist that bind the same receptor; however, they elicit unique host responses and display distinct potencies of antiviral activities. Our previous studies on human immunodeficiency virus (HIV) and hepatitis B virus (HBV) demonstrated that the clinically used IFNα2 is not the most effective one among the IFNα subtypes. By sequence modeling, we identified a region in helix B with mainly conserved residues at the outside facing IFNAR1, but variable residues at the inside facing the core of IFNα, potentially representing a putative tunable anchor to tune pleiotropic IFN responses. Using site-directed mutagenesis, various mutations were introduced into the IFNα2b backbone targeting sites which are important for binding to IFNAR1 and IFNAR2, the putative tunable anchor, or outside these three regions. Selected mutations were based on sequence differences to high antiviral subtypes IFNα6 and IFNα14. Treatment assays against HBV and HIV identified several critical residues for the antiviral activity of IFNα mainly in the IFNAR1 binding region. Combined mutations of the IFNα2 IFNAR1/2 binding sites or the IFNAR1 binding region plus the putative tunable anchor by those of IFNα14 further augmented activation of different downstream signaling cascades providing a molecular correlate for the enhanced antiviral activity. We describe here important functional residues within IFNα subtype molecules, which enabled us to design novel and innovative drugs that may have the potential to be used in clinical trials against a variety of different viral infections.IMPORTANCEThe potency of interferon (IFN)α to restrict viruses was already discovered in 1957. However, until today, only IFNα2 out of the 12 distinct human IFNα subtypes has been therapeutically used against chronic viral infections. There is convincing evidence that other IFNα subtypes are far more efficient than IFNα2 against many viruses. In order to identify critical antiviral residues within the IFNα subtype sequence, we designed hybrid molecules based on the IFNα2 backbone with individual sequence motifs from the more potent subtypes IFNα6 and IFNα14. In different antiviral assays with HIV or HBV, residues binding to IFNAR1 as well as combinations of residues in the IFNAR1 binding region, the putative tunable anchor, and residues outside these regions were identified to be crucial for the antiviral activity of IFNα. Thus, we designed artificial IFNα molecules, based on the clinically approved IFNα2 backbone, but with highly improved antiviral activity against several viruses.https://journals.asm.org/doi/10.1128/mbio.02357-23interferonshepatitis B virusantiviral therapyIFNARhuman immunodeficiency virus |
| spellingShingle | Zehra Karakoese Vu-Thuy Khanh Le-Trilling Jonas Schuhenn Sandra Francois Mengji Lu Jia Liu Mirko Trilling Daniel Hoffmann Ulf Dittmer Kathrin Sutter Targeted mutations in IFNα2 improve its antiviral activity against various viruses mBio interferons hepatitis B virus antiviral therapy IFNAR human immunodeficiency virus |
| title | Targeted mutations in IFNα2 improve its antiviral activity against various viruses |
| title_full | Targeted mutations in IFNα2 improve its antiviral activity against various viruses |
| title_fullStr | Targeted mutations in IFNα2 improve its antiviral activity against various viruses |
| title_full_unstemmed | Targeted mutations in IFNα2 improve its antiviral activity against various viruses |
| title_short | Targeted mutations in IFNα2 improve its antiviral activity against various viruses |
| title_sort | targeted mutations in ifnα2 improve its antiviral activity against various viruses |
| topic | interferons hepatitis B virus antiviral therapy IFNAR human immunodeficiency virus |
| url | https://journals.asm.org/doi/10.1128/mbio.02357-23 |
| work_keys_str_mv | AT zehrakarakoese targetedmutationsinifna2improveitsantiviralactivityagainstvariousviruses AT vuthuykhanhletrilling targetedmutationsinifna2improveitsantiviralactivityagainstvariousviruses AT jonasschuhenn targetedmutationsinifna2improveitsantiviralactivityagainstvariousviruses AT sandrafrancois targetedmutationsinifna2improveitsantiviralactivityagainstvariousviruses AT mengjilu targetedmutationsinifna2improveitsantiviralactivityagainstvariousviruses AT jialiu targetedmutationsinifna2improveitsantiviralactivityagainstvariousviruses AT mirkotrilling targetedmutationsinifna2improveitsantiviralactivityagainstvariousviruses AT danielhoffmann targetedmutationsinifna2improveitsantiviralactivityagainstvariousviruses AT ulfdittmer targetedmutationsinifna2improveitsantiviralactivityagainstvariousviruses AT kathrinsutter targetedmutationsinifna2improveitsantiviralactivityagainstvariousviruses |