CLASS II PHOSPHATIDYLINOSITOL 3-KINASE 2 beta IS A NOVEL TARGET FOR THE POTENTIAL DEVELOPMENT OF ANTIVIRAL DRUGS AGAINST THE HEPATITIS B VIRUS

Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that regulate crucial cellular processes, including cell survival, proliferation and intracellular vesicular trafficking. PI3Ksphosphorylate the 3-hydroxyl position of phosphatidylinositol (PI), PI(4)P and PI(4,5)P. Three PI3Ks classes have been described, according to their structure, substrate preference, and function, of which class II PI3Ks are least investigated. Class II PI3K comprises the PI3K-C2 alpha, PI3K-C2 beta, and PI3K-C2 gamma isoforms with different cellular localisations involved in vesicular trafficking. PI3K-C2 beta, in particular, regulates endocytosis and endosomal signalling and, therefore, could interfere with the life-cycle of viruses that depend on the endosomal pathway for trafficking and morphogenesis, such as the Hepatitis B virus (HBV). HBV is an important human pathogen causing severe liver disease and hepatocellular carcinoma development, which results in the death of more than 500.000 chronically-infected patients every year. In this study, we modulated PI3K-C2 beta expression in hepatoma cells by using the CRISPR/Cas9 genome editing technology and investigated the consequences on HBV production. Our results showed significant inhibition of HBV particles release from cells depleted of PI3K-C2 beta, adding to the repertoire of host cell factors regulating HBV production, a novel target for the potential development of antiviral inhibitors.