Measles virus reprograms CD4⁺ T-cell sphingolipid and fatty acid metabolism to facilitate infection

CD150-positive (CD150⁺) lymphocytes are the primary targets of measles virus (MV) infection during the acute phase. The depletion of infected CD150⁺ memory cells leads to a profound suppression of immune memory, resulting in increased susceptibility to secondary infections and severe complications in infected individuals. While lipids are known to be critical for viral life cycles, the specific lipid metabolic conditions facilitating MV replication in immune cells remain poorly understood.

In this study, a comprehensive lipidomic analysis of MV-infected primary CD4⁺ T cells revealed significant alterations in three major lipid classes: sphingolipids, triacylglycerols, and glycerophospholipids. Specifically, MV infection increased the abundance of ceramides, dihydroceramides and triacylglycerols, while significantly reducing the levels of glucosylceramides and glycerophospholipids. Pharmacological intervention in the pathways of de novo sphingolipid synthesis, triacylglycerol synthesis and lipolysis significantly impaired measles virus replication in activated CD4⁺ CD150⁺ T cells.

Mechanistically, we demonstrate that MV glycoprotein-mediated membrane fusion, essential for viral entry and cell-to-cell spread, requires glucosylceramide synthase (GCS) activity and is further promoted by plasma membrane triacylglycerol content. Collectively, these findings highlight the essential role of MV-modulated triacylglycerol and sphingolipid metabolism in viral entry, dissemination, and intracellular replication within CD4⁺ T cells.