Abstract
Herpes simplex virus 1 (HSV-1) is a widespread neurotropic virus establishing a life-long latent infection in neurons with periodic reactivations. Recent studies linked HSV-1 to neurodegenerative processes related to age-related disorders such as Alzheimer’s disease. Here, we explored whether recurrent HSV-1 infection might accelerate aging in neurons, focusing on peculiar marks of aged cells, such as the increase in histone H4 lysine (K) 16 acetylation (ac) (H4K16ac); the decrease of H3K56ac, and the modified expression of Sin3/HDAC1 and HIRA proteins. By exploiting both in vitro and in vivo models of recurrent HSV-1 infection, we found a significant increase in H4K16ac, Sin3, and HDAC1 levels, suggesting that the neuronal response to virus latency and reactivation includes the upregulation of these aging markers. On the contrary, we found a significant decrease in H3K56ac that was specifically linked to viral reactivation and apparently not related to aging-related markers. A complex modulation of HIRA expression and localization was found in the brain from HSV-1 infected mice suggesting a specific role of this protein in viral latency and reactivation. Overall, our results pointed out novel molecular mechanisms through which recurrent HSV-1 infection may affect neuronal aging, likely contributing to neurodegeneration.
Highlights
Herpes simplex virus 1 (HSV-1) is a neurotropic virus able to establish a life-long infection in neurons
24 hours (h) post-infection (p.i.) or 24 h post-viral reactivation (p.r.). The latter group of neurons was treated with 50 μM acycloguanosine (ACV) starting from 18 h before the virus or mock inoculation (Figure 1a) to allow the establishment of latent infection; 10 days postinfection (d.p.i.), neurons were subjected to thermal stress (TS; 10 min, 42 ◦ C) in the absence of ACV to induce HSV-1 reactivation, as described in Materials and Methods
We addressed the hypothesis that recurrent HSV-1 infection may accelerate brain aging
Summary
HSV-1 is a neurotropic virus able to establish a life-long infection in neurons. After a primary infection in the epithelial cells, the virus contacts the axonal endings of sensory and sympathetic neurons in the site of primary infection [1,2] and, via retrograde axonal transport, reaches the cell bodies in the ganglia of the peripheral nervous system (PNS)where it establishes a latent infection. Successful reactivation allows the production of new viral particles that, traveling along the axon, return to the primary infection site (e.g., oral mucosal epithelial cells) and give rise to recurrent infection (symptomatic or asymptomatic) These viral particles may reach the central nervous system (CNS) where they can infect neurons causing a severe herpetic encephalitis or, likely, establishing a latent infection [1,3,4,5]. An increasing body of data pointed out herpesviruses infections, such as HSV-1, as co-risk factors in the CNS neurodegenerative diseases, including Alzheimer’s disease (AD), the main form of dementia in the elderly [1,6,7,8,9,10,11,12,13,14,15]. We observed a correlation between the number of viral reactivations and the progressive accumulation of these markers in HSV-1-infected mice compared to control ones
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