Resumo

The pathogenic mechanisms of Herpes Simplex Virus type 1 (HSV-1) at the central nervous system (CNS) are not well known, however, data suggest that HSV-1 is able to establish latency in the CNS in humans, and that this condition would not be harmless. In addition, it has been estimated that in approximately 70% of the population over 50 years old, the virus enters the brain and infects neurons, suggesting the existence of recurrent reactivations. Currently, it is unclear whether a neuron, that undergoes viral reactivation and produces infectious particles, survives and resumes latency or is killed. 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 sensor Sirtuin 1 (Sirt1) is involved in neuronal survival and neuroprotection we hypothesized that HSV-1 virus could activate Sirt1 as a strategy to establish latency by means of inhibiting apoptosis and restoring energy homeostasis through deacetylation of the pro-apoptotic protein p53 and regulation of the expression of the master regulator of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor  coactivator 1α (PGC-1α) and its target gene TFAM. Therefore, we evaluated the expression of Sirt1 and its effect on the downstream targets p53 and PGC-1α, in mice neuronal cultures infected with HSV-1 through western blot, RT-PCR and immunofluorescence analyses. Here we show that HSV-1 infection activates Sirt1 resulting in a reduction of acetylated-p53 and an increase in PGC-1α expression at 4 hours post infection. Interestingly, immunofluorescence analyses show an increase in acetylated-p53 in neurons adjacent to infected neurons after longer infection periods and before neuronal death takes place. These results suggest that HSV-1 modulates Sirt1-dependent pathways in neurons at early times post infection interfering with the pro-apoptotic response. Funding FONDECYT 1120464.