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

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.

Hijacking of the Ubiquitin/Proteasome Pathway by the HIV Auxiliary Proteins

“…For instance, in the herpesviridae family, a variety of DUBs play an important role in the virus life cycle (e.g., UL36USP (Ubiquitin Ligase 36 Ubiquitin Specific Protease) of HSV-1, tegument protein pUL48 of human cytomegalovirus (HCMV)). Regarding HIV-1, a recent study reported that several cellular DUBs (USP7 and USP47, Ubiquitin Specific Protease family) play an important role in its replication by regulating Gag processing and thus the infectivity of released virions and simultaneously the entry of Gag into the UPS and MHC-I pathway [ 39 ]. Moreover, this study showed that treatment with DUB inhibitors targeting USP47 causes a general Gag processing defect, indicating that USP47 interacts with Gag and prevents its entry into the UPS.…”

The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE

“…Furthermore, we analyzed the stability of p6 derived from the X4-tropic HIV-1 field isolate 4lig7. This isolate also belongs to the subtype B and is known for several resistance mutations within the reverse transcriptase (RT) and the protease (PR) open reading frame, causing resistance to all nucleoside RT inhibitors and to most PR inhibitors [57].…”

Gga-miR-30d regulates infectious bronchitis virus infection by targeting USP47 in HD11 cells

“…Besides, USP47 also plays an important role in innate immunity. It has been reported that P22077, a selective ubiquitin-specific protease 7/47 (USP7/ USP47) inhibitor, inhibited the proliferation of HIV virus by inhibiting the function of USP47 [27].…”