Herpes simplex virus type 1 (HSV-1) is a neurotropic virus able to establish a persistent latent infection in the host. Herpes simplex encephalitis (HSE) is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. Currently, it is unclear whether asymptomatic recurrent reactivations of HSV-1 occur in the central nervous systems in infected people, and if these events could lead to a progressive deterioration of neuronal function. In this context, HSV-1 constitutes an important candidate to be included among the risk factors for the development of Alzheimer's disease. Our group have demonstrated that HSV-1 triggers neurodegenerative events in in vitro and in vivo induced neuronal infection, evidenced by increase in tau hyperphosphorylation and caspase-3 dependent cleavage of tau protein, resembling what occurs in neurodegenerative diseases. In addition, in an in vivo model, a reactivation episode during asymptomatic latency of HSV-1 infection in mice was accompanied by upregulation of neuroinflammatory markers (toll-like receptor-4, interferon /β, and p-IRF3). Besides, previous reports have shown that HSV-1 inhibits apoptosis during early infection, but is pro-apoptotic during productive infection. Taking in consideration that the stress sensors AMPK and Sirt1 are involved in neuronal survival and neuroprotection, we hypothesized that HSV-1 could activate the AMPK/Sirt1 axis as a strategy to establish latency through inhibition of apoptosis and restoration of the energy status. Thus, we demonstrated that HSV-1 modulates the AMPK/Sirt1 axis differentially during infection, interfering with pro-apoptotic signaling and regulating mitochondrial biogenesis, pivotal processes in the lifetime of neurons in the central nervous system. In conclusion, our findings support the idea that HSV-1 could contribute to induce neurodegenerative processes in age-associated pathologies such as Alzheimer's disease.