The impact of fatty acid synthase on HSV-1 infection dynamics

Abstract

Herpes simplex virus type-1 (HSV-1) is a widespread human pathogen that relies on host cell pathways, including those involved in metabolism to support replication. Here, we demonstrate that de novo lipogenesis is essential for HSV-1 infectivity. Specifically, HSV-1 infection upregulates fatty acid synthase (FASN) expression, accompanied by a marked increase in lipids and a differential lipid species distribution. Conversely, silencing FASN or applying FASN inhibitors (i.e., CMS121 and C75) markedly reduces the infectivity of newly released HSV-1 virions, suggesting that while initial replication remains unaffected, FASN is crucial for maintaining virion structure and facilitating entry into host cells. Additionally, we show that a source of lipid-rich external factors provided by fetal bovine serum significantly increases HSV-1 infectivity. Specifically, HSV-1 infection enhanced CD36-mediated fatty acid uptake, especially in FASN-depleted cells, compensating for reduced lipogenesis. Blocking CD36 function with SSO further decreased viral infectivity, demonstrating the critical role of lipid uptake in HSV-1 life cycle. Altogether, our findings reveal how HSV-1 manipulates lipid metabolism, offering insights into its association with chronic disease and therapeutic intervention.