Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes
In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)—the proteasome holoenzymes and a number of ubiquitin ligases—play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodefic...
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MDPI AG
2017-08-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/9/8/222 |
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| author | Christian Setz Melanie Friedrich Pia Rauch Kirsten Fraedrich Alina Matthaei Maximilian Traxdorf Ulrich Schubert |
| author_facet | Christian Setz Melanie Friedrich Pia Rauch Kirsten Fraedrich Alina Matthaei Maximilian Traxdorf Ulrich Schubert |
| author_sort | Christian Setz |
| collection | DOAJ |
| description | In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)—the proteasome holoenzymes and a number of ubiquitin ligases—play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodeficiency virus type 1 (HIV-1). However, the role in HIV-1 replication of the third major component, the deubiquitinating enzymes (DUBs), has remained largely unknown. In this study, we show that the DUB-inhibitors (DIs) P22077 and PR-619, specific for the DUBs USP7 and USP47, impair Gag processing and thereby reduce the infectivity of released virions without affecting viral protease activity. Furthermore, the replication capacity of X4- and R5-tropic HIV-1NL4-3 in human lymphatic tissue is decreased upon treatment with these inhibitors without affecting cell viability. Most strikingly, combinatory treatment with DIs and proteasome inhibitors synergistically blocks virus replication at concentrations where mono-treatment was ineffective, indicating that DIs can boost the therapeutic effect of proteasome inhibitors. In addition, P22077 and PR-619 increase the polyubiquitination of Gag and thus its entry into the UPS and the major histocompatibility complex (MHC)-I pathway. In summary, our data point towards a model in which specific inhibitors of DUBs not only interfere with virus spread but also increase the immune recognition of HIV-1 expressing cells. |
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| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-12-23T03:32:31Z |
| publishDate | 2017-08-01 |
| publisher | MDPI AG |
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| series | Viruses |
| spelling | doaj.art-70df03217bc849728e8caf64404a3fa62022-12-21T18:01:38ZengMDPI AGViruses1999-49152017-08-019822210.3390/v9080222v9080222Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I EpitopesChristian Setz0Melanie Friedrich1Pia Rauch2Kirsten Fraedrich3Alina Matthaei4Maximilian Traxdorf5Ulrich Schubert6Institute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, GermanyInstitute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, GermanyInstitute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, GermanyInstitute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, GermanyInstitute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, GermanyDepartment of Otorhinolaryngology, Head and Neck Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, GermanyInstitute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, GermanyIn recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)—the proteasome holoenzymes and a number of ubiquitin ligases—play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodeficiency virus type 1 (HIV-1). However, the role in HIV-1 replication of the third major component, the deubiquitinating enzymes (DUBs), has remained largely unknown. In this study, we show that the DUB-inhibitors (DIs) P22077 and PR-619, specific for the DUBs USP7 and USP47, impair Gag processing and thereby reduce the infectivity of released virions without affecting viral protease activity. Furthermore, the replication capacity of X4- and R5-tropic HIV-1NL4-3 in human lymphatic tissue is decreased upon treatment with these inhibitors without affecting cell viability. Most strikingly, combinatory treatment with DIs and proteasome inhibitors synergistically blocks virus replication at concentrations where mono-treatment was ineffective, indicating that DIs can boost the therapeutic effect of proteasome inhibitors. In addition, P22077 and PR-619 increase the polyubiquitination of Gag and thus its entry into the UPS and the major histocompatibility complex (MHC)-I pathway. In summary, our data point towards a model in which specific inhibitors of DUBs not only interfere with virus spread but also increase the immune recognition of HIV-1 expressing cells.https://www.mdpi.com/1999-4915/9/8/222HIV-1DUB-inhibitorsUPSDUBsubiquitinationMHC-Iproteasome inhibitors |
| spellingShingle | Christian Setz Melanie Friedrich Pia Rauch Kirsten Fraedrich Alina Matthaei Maximilian Traxdorf Ulrich Schubert Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes Viruses HIV-1 DUB-inhibitors UPS DUBs ubiquitination MHC-I proteasome inhibitors |
| title | Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes |
| title_full | Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes |
| title_fullStr | Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes |
| title_full_unstemmed | Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes |
| title_short | Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes |
| title_sort | inhibitors of deubiquitinating enzymes block hiv 1 replication and augment the presentation of gag derived mhc i epitopes |
| topic | HIV-1 DUB-inhibitors UPS DUBs ubiquitination MHC-I proteasome inhibitors |
| url | https://www.mdpi.com/1999-4915/9/8/222 |
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