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1.
Immunology ; 159(3): 309-321, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31691271

RESUMO

Type-I interferons (IFN-I) are used as common antiviral drugs for a range of viral diseases in clinic. However, the antiviral efficacy of IFN-I is largely restricted by negative regulators of IFN-I signaling in cells. Therefore, identification of intracellular inhibitors of IFN-I signaling is important for developing novel targets to improve IFN-I antiviral therapy. In this study, we report that the deubiquitinase ubiquitin-specific protease 7 (USP7) negatively regulates IFN-I-mediated antiviral activity. USP7 physically interacts with suppressor of cytokine signaling 1 (SOCS1) and enhances SOCS1 protein stability by deubiquitination effects, which in turn restricts IFN-I-induced activation of Janus kinase-signal transducer and activator of transcription 1 signaling. Interestingly, viral infection up-regulates USP7 and therefore facilitates viral immune evasion. Importantly, the USP7 small-molecule inhibitors P5091 and P22077 inhibit SOCS1 expression and enhance IFN-I antiviral efficacy. Our findings identify a novel regulator of IFN-I antiviral activity and reveal that USP7 inhibitors could be potential enhancement agents for improving IFN-I antiviral therapy.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Interferon-alfa/farmacologia , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Tiofenos/farmacologia , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Vesiculovirus/efeitos dos fármacos , Células A549 , Células HEK293 , Células HeLa , Interações Hospedeiro-Patógeno , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Janus Quinases/metabolismo , Ligação Proteica , Estabilidade Proteica , Proteólise , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/genética , Fatores de Tempo , Peptidase 7 Específica de Ubiquitina/metabolismo , Ubiquitinação , Vesiculovirus/imunologia , Vesiculovirus/patogenicidade
2.
Viral Immunol ; 30(3): 224-231, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28005469

RESUMO

Programmed death-1 (PD-1) expression has been revealed to be upregulated on T cells and contributes to T cell exhaustion in patients with hepatitis B virus (HBV) infection. In this study, we investigated the dynamic expression of programmed death ligand-1 (PD-L1), the ligand of PD-1, on circulating CD14+ monocytes and CD19+ B cells of HBV-infected patients at the stages of chronic HBV (CHB) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC), respectively. The results showed that compared with healthy controls, the levels of PD-L1 expression on CD14+ and CD19+ populations were both upregulated in CHB, LC, and HCC groups. Although there was no significant difference of PD-L1 expression on CD14+ population among three disease groups, further analysis demonstrated that the frequency of CD14+PD-L1+ population was negatively correlated with HBV DNA load, the levels of alanine aminotransaminase (ALT), and the levels of aspartate aminotransferase (AST), respectively, at CHB stage, while it did not present significant correlation with such parameters at LC stage and was only positively correlated with HBV DNA load at HCC stage. Similarly, the levels of PD-L1 expression on CD19+ population also did not present much difference among three disease groups. Intriguingly, the frequencies of CD19+PD-L1+ population at CHB and LCC stages were both positively correlated with the levels of ALT and AST, but they were not significantly correlated with HBV DNA load. Thereby, the current study elucidated the dynamics of PD-L1 expression on monocytes and B cells, along with the dynamic regulation of PD-1 on T cells, which had a close relationship during the progression of HBV infection. Collectively, our findings demonstrated that in the course of HBV infection development, PD-L1 expression on CD14+ monocytes and CD19+ B cells varied and significantly correlated with clinical parameters, which could be utilized as a potential clinical indicator.


Assuntos
Linfócitos B/química , Antígeno B7-H1/análise , Carcinoma Hepatocelular/patologia , Hepatite B Crônica/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Monócitos/química , Adulto , Alanina Transaminase/sangue , Antígenos CD19/análise , Aspartato Aminotransferases/sangue , DNA Viral/sangue , Feminino , Hepatite B Crônica/complicações , Humanos , Receptores de Lipopolissacarídeos/análise , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Prognóstico , Carga Viral
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