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Sirtuin 1-chromatin-binding dynamics point to a common mechanism regulating microglial inflammatory targets in SIV infection and in the aging brain

ABSTRACT: Microglia are critical regulators in neurodegenerative disorders. Since HIV infection results in neurological perturbations that are similar to those in aging, we examined microglial changes that might resemble aging, using SIV infection in rhesus macaques to model neuroAIDS. We found that Sirt-1, a molecule that impacts survival and health in many models, was decreased in infected macaques. The role of Sirt-1 in neuroAIDS is unknown. We hypothesized that Sirt-1 silencing functions are affected by SIV. Mapping of Sirt-1 binding patterns to chromatin revealed that the number of Sirt-1-bound genes was 29.6% increased in microglia from infected animals with mild neuropathology, but 51% was decreased in severe neuropathology, compared to controls. Sirt-1-bound genes in controls largely participate on neuroinflammation. Promoters of type I IFN pathway genes IRF7, IRF1, IFIT1, and AIF1, showed Sirt-1 binding in controls, which was consistently lost after infection, together with higher transcription. This was also found in brains from old uninfected animals, suggesting a common regulation. Sirt-1 blockage in vitro modulated IRF7, IRF1 and AIF1 levels. Our data suggests that Sirt-1-inflammatory gene silencing is disturbed by SIV, resembling aging in brains. These findings may impact neurological consequences of HIV infection, aggravated and overlapping with the aging process.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE95793 | GEO | 2017/03/22

SECONDARY ACCESSION(S): PRJNA378414

REPOSITORIES: GEO

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Sirtuin 1-chromatin-binding dynamics point to a common mechanism regulating microglial inflammatory targets in SIV infection and in the aging brain

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