Recurrent Herpes Simplex Virus type 1 infection modulates aging-related epigenetic markers in mouse brains

Aging is one of the major risk factors for Alzheimer's Disease (AD). At the brain level, this process is characterized by a slow, time-dependent change of multiple physiological functions and cognitive decline. Genome instability, together with changes in gene expression, driven by epigenetic imbalance, are the main features of neuronal senescence. Recent data from our group showed that recurrent Herpes Simplex Virus 1 (HSV-1) infection in mice induces an accumulation of AD hallmarks, including amyloid-? and tau hyperphosphorylation, paralleled by irreversible cognitive deficits. In this scenario, we hypothesized that recurrent HSV-1 infection may also accelerate the normal brain aging, by affecting epigenetic mechanisms. To verify this hypothesis, we evaluated the levels of specific aging hallmarks, such as histone 3 deacetylation (i.e., at H3K56), in mouse experimental models of acute and recurrent virus infection. We also analysed the expression of two key epigenetic regulators, such as Sin3/HDAC1 complex, and the histone chaperone HIRA, both involved also in the regulation of HSV-1 life-cycle and viral-host interaction. To these aims, entorhinal cortex homogenates from HSV-1- and Mock-infected BALB/c female mice were analysed in western blot for H3K56 acetylation, and HIRA and Sin3/HDAC1 expression. A group of mice was analysed 4 days post primary infection (dpi), whereas the others were subjected to multiple thermal stress (TSs) every 6 weeks, to induce repeated virus reactivations. 5 mice for group were sacrificed after the 3rd and the 7th TS. A group of 4 mice were sacrificed just before the 7th TS (during latent infection). The virus presence in the brain was assessed by molecular analysis of viral gene/protein expression as well as by virological methods. We found that TS-induced virus replication caused in mouse brain a significant decrease in H3K56 acetylation (p<0,05 post-3TS; p<0,01 post-7TS) as compared to those observed in Mock-infected mice, suggesting that the infection impairs the histone acetylation process. Accordingly, we found a significant increase in Sin3/HDAC1 protein expression levels with respect to matched Mock-infected mice, starting from 4 dpi (p<0,05). A similar increase was observed following 7 TSs (p<0,05). Notably, these effects, together with a significant increase in HIRA protein levels, were found also in those mice sacrificed before the 7th TS, indicating that epigenetic imbalance may persist over time. Overall these data strongly suggest that recurrent HSV-1 infection enhances cellular epigenetic aging and may wider affect the epigenetic landscape in mice.