Exploiting Lipid Metabolism by HSV-1: a Challenge to Rethink New Therapies for Alzheimer’s Disease

Herpes simplex virus-1 (HSV-1) establishes a life-long latent infection and can enter the brain via retrograde axonal transport. Recurrent reactivation of HSV-1 may lead to neurodegenerative disorders, including Alzheimer’s disease (AD), although the underlying mechanisms have not been fully elucidated yet. Lipids constitute the bulk of the brain dry mass and alteration of lipid metabolism is a key component in AD. Recently, CMS121 was shown to protect transgenic AD mice by reducing cognitive loss and inflammation. Interestingly, FAS (fatty acid synthase), a key enzyme in the synthesis of lipids that is increased in AD patients, was identified as a target of CMS121. FAS inhibition through CMS121 protects against lipid peroxidation and neuroinflammation, linking perturbed lipid metabolism to neurodegeneration. Considering that cellular lipid metabolism plays a pivotal role in viral infection and that the mechanisms for the metabolic reprogramming by HSV-1 are still poorly understood, we aim at dissecting the host metabolic pathways modulated by HSV-1 in a neuronal-like cell line to identify crucial pathways that might be targeted to prevent HSV-1-driven AD. Specifically, we found an increase in both de novo synthesis and lipid storage following HSV-1 infection. In addition, we demonstrated that the anti-AD compounds targeting lipid metabolism (i.e. CMS121, C75) impaired HSV-1 infectivity. Moreover, to better understand the link between FAS and HSV-1 infectivity, we suppressed FAS expression by short hairpin RNA (shRNA) (shFASN) and validated the results obtained with the compounds, ruling out any off-target effects. Overall, our data unveil new aspects of HSV-1-AD interplay and uncover new potential targets to rethink new possible therapies.