Poliovirus evolution towards independence from the phosphatidylinositol-4 kinase III β/oxysterol-binding protein family I pathway

Description

Phosphatidylinositol-4 kinase III β (PI4KB) and oxysterol-binding protein (OSBP) family I provide a conserved host pathway required for enterovirusreplication. Here, we analyze the role and essentiality of this pathway in enterovirus replication. Phosphatidylinositol 4-phosphate (PI4P) production and cholesterol accumulation in the replication organelle (RO) are severely suppressed in cells infected with a poliovirus (PV) mutant isolated from a PI4KB-knockout cell line (RD[ΔPI4KB]). Major determinants of the mutant for infectivityin RD(ΔPI4KB) cells map to the A5270U(3A-R54W) and U3881C(2B-F17) mutations. The 3Amutation is required for PI4KB-independent development of RO. The 2Bmutation rather sensitizes PV to PI4KB/OSBP inhibitors by itself, but conferssubstantially complete resistance to theinhibitorswith the 3Amutation, suggesting that the PI4KB/OSBP pathway is not necessarily essential for enterovirus replication in vitro. This work supports a two-step resistance model of enterovirus, and offers insights into a potential evolutionary pathway of enterovirus towards independence from the PI4KB/OSBP pathway

Abstract

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