The role of HSV1 infection in brain epigenetic aging

Introduction. Aging is naturally characterized by time-dependent deterioration of multiple biological and cellular functions, and complex molecular changes, including epigenetic post translational modifications (PTMs), are hallmarks of aging. Deregulation in the acetylation levels may be involved in various pathologies, including cancer, viral infections and neurodegenerative diseases. Herpes Simplex Virus type-1 (HSV-1), a neurotropic virus capable to establish a latent infection in the host trigeminal ganglia and able to reach the brain following reactivations, is known to interact with host epigenetic complexes, but several aspects have yet to be clarified. This study was aimed to investigate the influence of HSV-1 on the host epigenetic aging in the brain, by evaluating specific PTM levels in in vitro and in vivo experimental models of acute and recurrent HSV-1 infection. Materials and Methods. Primary cultures of neuronal cells were obtained by E17 rat embryo brains and, after 7 days in vitro, infected with HSV-1(0.1 multiplicity of infection) or MOCK solution, then analysed by Western Blot (WB) at 24h (acute infection) or 8 days post-infection (p.i.) to evaluate H3K56 and H4K16 acetylation levels. Long-term infection was obtained treating neurons with Acyclovir (before, during and after infection) to induce virus latency. Entorhinal cortex homogenates from BALB/c mice were analysed in WB for H3K56 and H4K16 acetylation levels. These mice were HSV1 or MOCK inoculated at 2 months of age, and then subjected to several hyperthermia cycles to induce virus reactivations over their life and sacrificed at 13 months of age. The virus presence in the brain was tested by PCR and RT-PCR analysis of viral TK and ICP4 genes, and IF analysis of gB protein expression. Results. We found that HSV1 modulates the levels of H3K56 and H4K16 acetylation during acute infection in neuronal cell cultures. Furthermore, a decrease in acetylation levels of H3K56 was found 8 days p.i. and similar effects were found following recurrent infections in mice. On the contrary, H4K16 acetylation was found only slightly altered in both models. Discussion and Conclusions. These results indicate that HSV-1 infection induce a modulation in H3K56 acetylation during long-term infections, and suggest that the virus may promote epigenetic aging. Further studies will be focused on characterizing how the virus could act on age-related epigenetic hallmarks.