Polo-like-kinase 1 is a proviral host-factor for hepatitis B virus replication

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Diab, A.M. | Foca, A. | Fusil, F. | Lahlali, T. | Jalaguier, P. | Amirache, F. | N'Guyen, L. | Isorce, N. | François-Loïc, Cosset | Zoulim, Fabien | Andrisani, O.M. | Durantel, David

Edité par CCSD ; Wiley-Blackwell -

International audience. Chronic Hepatitis B Virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) and current treatments for CHB and HCC are perfectible. Herein, we identified cellular Serine/Threonine Polo-like-kinase 1 (PLK1) as a positive effector of HBV replication. The aim of this study was to demonstrate the proviral role of PLK1 in HBV biosynthesis and validate PLK1 inhibition a potential antiviral strategy. To this end, we employed physiologically relevant HBV infection models of Primary Human Hepatocytes (PHH) and differentiated HepaRG cells, in conjunction with pharmacologic PLK1 inhibitors, siRNA-mediated knockdown, and overexpression of constitutively active PLK1 (PLK1CA ). In addition, humanized liver FRG mouse model was used to determine antiviral effect of PLK1 inhibitor BI-2536 on HBV infection in vivo. Lastly, in vitro PLK1 kinase assays and site-directed mutagenesis were employed to demonstrate HBV core protein (HBc) is a PLK1 substrate. We demonstrate HBV infection activated cellular PLK1 in PHH and dHepaRG cells. PLK1 inhibition by BI-2536 or siRNA-mediated knockdown suppressed, whereas overexpression of PLK1CA increased HBV DNA biosynthesis, supporting PLK1 effects on viral biosynthesis are specific, and PLK1 is a proviral cellular factor. Significantly, BI-2536 administration to HBV-infected humanized liver FRG mice strongly inhibited HBV infection, validating PLK1 as a novel antiviral target in vivo. The proviral action of PLK1 is associated with the biogenesis of the nucleocapsid, as BI-2536 leads to its decreased intracellular formation/accumulation. In this respect, our studies identified HBc as a PLK1 substrate in vitro, and mapped PLK1 phosphorylation sites on this protein. PLK1 is a proviral host factor that could be envisaged as a target for combined antiviral and anti-tumoral strategies against HBV infection and HBV mediated carcinogenesis. This article is protected by copyright. All rights reserved

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