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Viruses 2017, 9(8), 222; doi:10.3390/v9080222

Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes

1
Institute of Virology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany
2
Department of Otorhinolaryngology, Head and Neck Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editors: Jason B. Weinberg and Jaquelin Dudley
Received: 2 June 2017 / Revised: 4 August 2017 / Accepted: 8 August 2017 / Published: 12 August 2017
(This article belongs to the Special Issue Viruses, ERAD, and the Proteasome)
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Abstract

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. View Full-Text
Keywords: HIV-1; DUB-inhibitors; UPS; DUBs; ubiquitination; MHC-I; proteasome inhibitors HIV-1; DUB-inhibitors; UPS; DUBs; ubiquitination; MHC-I; proteasome inhibitors
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Setz, C.; Friedrich, M.; Rauch, P.; Fraedrich, K.; Matthaei, A.; Traxdorf, M.; Schubert, U. Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes. Viruses 2017, 9, 222.

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