DISTINCT STRATEGIES OF LIPID METABOLIC EXPLOITATION BY HSV-1 AND HCMV

Herpesviruses are ubiquitous double-stranded DNA viruses characterized by the ability to establish lifelong infections through latency and periodic reactivation. Among human herpesviruses, herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV) are widespread pathogens associated with a considerable clinical burden. This thesis investigates the role of host lipid metabolism in herpesvirus infection, with particular focus on de novo fatty acid synthesis and fatty acid synthase (FASN). Increasing evidence indicates that viruses actively reprogram host metabolic networks to support replication and virion production; however, the precise contribution of lipid biosynthesis to herpesvirus infectivity remains debated. In HSV-1 infection, de novo lipogenesis emerges as a critical determinant of viral infectivity. HSV-1 induces a strong upregulation of FASN expression accompanied by extensive lipid remodeling. Moreover, genetic silencing of FASN or pharmacological inhibition with CMS121 and C75 markedly reduces the infectivity of newly produced virions. Transmission electron microscopy reveals compromised viral envelope integrity under FASN-inhibitory conditions, while the entry of progeny virions into target cells is impaired. These findings indicate that FASN-dependent lipogenesis is essential at post-replicative stages, where it preserves envelope integrity and ensures the production of structurally stable and fully infectious viral particles. HSV-1 further compensates for impaired lipogenesis by enhancing CD36-mediated uptake of extracellular fatty acids, highlighting a dual reliance on both endogenous lipid synthesis and exogenous lipid acquisition. Collectively, these results identify FASN as a critical host factor regulating virion integrity and infectivity and suggest lipid metabolism as a potential target for antiviral intervention. A distinct but convergent mechanism emerges from the analysis of HCMV infection. This work identifies a functional link between lipid metabolism and innate immune signaling, demonstrating that activation of the cGAS-STING pathway suppresses de novo lipogenesis by reducing FASN expression and enzymatic activity. The HCMV tegument protein pp65 counteracts this restriction by antagonizing cGAS-STING signaling. Although no differences in viral replication or infectivity are observed between wild-type HCMV and a pp65-deficient mutant under MOI-controlled conditions, genome-normalized infection reveals a significant reduction in infectivity of the pp65-deficient virus. This phenotype is associated with decreased lipid synthesis and reduced FASN expression and activity. Importantly, silencing cGAS or STING restores both viral infectivity and lipid synthesis in the absence of pp65. Together, these results demonstrate that pp65 promotes viral infectivity by relieving cGAS-STING-dependent metabolic repression, identifying a direct link between immune evasion and lipid metabolic reprogramming during HCMV infection. Overall, these findings establish lipid metabolism as a central determinant of herpesvirus infectivity and identify FASN as a shared host dependency exploited by both HSV-1 and HCMV through distinct mechanisms. HSV-1 relies on FASN-dependent lipogenesis to preserve virion structural integrity, whereas HCMV sustains lipid biosynthesis by modulating innate immune signaling through the cGAS-STING pathway. These results suggest that targeting metabolic pathways may represent a promising strategy for host-directed antiviral interventions.