Saturated Very Long Chain Fatty Acids Are Required for the Production of Infectious Human Cytomegalovirus Progeny

Abstract

Human cytomegalovirus hijacks host cell metabolism, increasing the flux of carbon from glucose to malonyl-CoA, the committed precursor to fatty acid synthesis and elongation. Inhibition of acetyl-CoA carboxylase blocks the production of progeny virus. To probe further the role of fatty acid metabolism during infection, we performed an siRNA screen to identify host cell metabolic enzymes needed for the production of infectious cytomegalovirus progeny. The screen predicted that multiple long chain acyl-CoA synthetases and fatty acid elongases are needed during infection, and the levels of RNAs encoding several of these enzymes were upregulated by the virus. Roles for acyl-CoA synthetases and elongases during infection were confirmed by using small molecule antagonists. Consistent with a role for these enzymes, mass spectrometry-based fatty acid analysis with¹³C-labeling revealed that malonyl-CoA is consumed by elongases to produce very long chain fatty acids, generating an approximately 8-fold increase in C26-C34 fatty acid tails in infected cells. The virion envelope was yet further enriched in C26-C34 saturated fatty acids, and elongase inhibitors caused the production of virions with lower levels of these fatty acids and markedly reduced infectivity. These results reveal a dependence of cytomegalovirus on very long chain fatty acid metabolism. Herpes viruses modulate cellular pathways to generate the building blocks that are necessary for their replication. Human cytomegalovirus alters metabolism of infected cells and causes a dramatic increase in lipid biosynthesis. We have investigated the role of lipid pathways in the viral life cycle and discovered that the virus requires several host enzymes that are responsible for the synthesis of very long chain fatty acids. Interestingly, very long chain fatty acids are substantially increased in the lipids of infected cells and saturated forms of these fatty acids are selectively incorporated into the envelope of the virus. Drugs that inhibit the synthesis of very long chain fatty acids generate virus particles with reduced infectivity. The discovery that human cytomegalovirus depends on the production of particular fatty acids furthers our understanding of virus-host cell interaction and suggests potential novel strategies for antiviral therapies.