Mechanism of Poliovirus Resistance to Host Phosphatidylinositol-4 Kinase III β Inhibitor.
Phosphatidylinositol-4 kinase III β (PI4KB) and oxysterol-binding protein (OSBP) family I have been identified as the major targets of anti-enterovirus drug candidates. Resistance mutations in poliovirus (PV) to these inhibitors have been identified in viral 3A protein, represented by a G5318A (3A-Ala70Thr) mutation, but the mechanism of viral resistance to host PI4KB/OSBP inhibitors remained unknown. In this study, we found that a G5318A mutation enhances the basal levels of phosphatidylinositol 4-phosphate (PI4P) and of the 3A protein and decreases the levels of the 3AB protein during PV replication. The 3A protein acted as a major effector responsible for the resistance to PI4KB inhibitor, but did not enhance the PI4KB activity in vitro in contrast to the 2C, 2BC, 3AB, and 3D proteins. The 3AB protein acted as the primary target of a G5318A mutation and also as an effector. We identified novel resistance mutations to a PI4KB inhibitor [C5151U (3A-T14M) and C5366U (3A-H86Y) mutations] and found that there is a positive correlation between the extent of the resistance phenotype and the levels of the 3A proteins. These results suggested that the 3A protein overproduced by enhanced processing of the 3AB protein with the resistance mutations overcomes the inhibitory effect of PI4KB inhibitor on PV replication independently of the hyperactivation of the PI4KB/OSBP pathway.
Department of Virology II, National Institute of Infectious Diseases , 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan.
Minetaro
M
Arita
D000998:Antiviral Agents / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics*; D054884:Host-Pathogen Interactions; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011051:Poliomyelitis / Q000188:drug therapy* / Q000821:virology*; D017955:Poliovirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects; D000098825:Oxysterol Binding Proteins
D000998:Antiviral Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D012367:RNA, Viral; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; C581087:PI4KB protein, human
PI4KB; enterovirus; inhibitor; poliovirus; resistance