Sirt-1-mediated regulation of NeuroAIDS In the post anti-retrovirals (ART) era, human immunodeficiency virus (HIV) infection is no longer a deadly condition. Rather, HIV+ individuals age with the chronic infection. Therefore, the consequences of HIV infection overlap and synergize with normal senescence in various organs, especially the brain. It is accepted that HIV infection triggers in the Central Nervous System (CNS) several hallmarks of aging, such as cognitive and motor disorders and dementia, regardless of CD4 levels1. However, the molecular aspects underlining this accelerated aging process in HIV-infected brains are poorly understood. Here, using the non-human primate model of neuroAIDS, SIV infection of rhesus macaques, we will provide preliminary evidence that the infection triggers molecular markers that were previously associated to aging in humans. We propose to explore the hypothesis that the virus causes a disruption of an epigenetic pathway that regulates aging and lifespan, which can be responsible for enhancing molecules that aggravate the inflammatory phenotype associated with CNS functional decay, ultimately represented by encephalitis. In this proposal we will address an important problem of how HIV promotes a rapid aging of the brain though a potential dysregulation of transcription, centered and orchestrated by the levels and function of Sirt-1, which is a molecule with profound implications to lifespan and in aging models. We studied the dynamics of Sirt-1 binding to chromatin in microglia from control and SIV-infected macaques, and identified a network of genes regulated by Sirt-1. Narrowing our analysis to in-promoter Sirt-1 binding sites, we generated a list of molecules that may have a critical role in the development of an inflammatory phenotype in the brain. In this application, we aim at examining the role of this network of molecules in depth, integrating CNS dysfunction and age, to understand the molecular and mechanistic basis for deep changes in the inflammatory environment that are common to aging and to HIV infection, and that synergize to aggravate neurological syndromes, even in the post- ART era.
Sirt-1-mediated regulation of NeuroAIDS In the post anti-retrovirals (ART) era, human immunodeficiency virus (HIV) infection is no longer a deadly condition and HIV+ individuals age with the chronic infection, in which the consequences of HIV infection overlap and synergize with normal senescence in organs such as the brain. In the brain of SIV-infected rhesus macaques, we found that the infection triggers molecular markers that were previously associated to aging in humans, and a drastic decrease in the levels and function of Sirt-1, a molecule with profound implications in aging models. Following up with preliminary studies determining genome-wide Sirt-1 targets in microglia, we propose to map and quantify genes putatively regulated by Sirt-1 in the brain, and to examine the role of Sirt-1-mediated regulation of gene transcription in microglia, as a strategy to establish the relationship between Sirt-1 histone targets in CNS pathology and age, and to better understand the molecular basis for deep changes that are common to aging and to HIV infection, and that synergize to aggravate neurological syndromes, even in the post ART era.
| Bortell, Nikki; Basova, Liana; Najera, Julia A et al. (2018) Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain. J Neuroimmune Pharmacol 13:163-178 |
| Bortell, Nikki; Basova, Liana; Semenova, Svetlana et al. (2017) Astrocyte-specific overexpressed gene signatures in response to methamphetamine exposure in vitro. J Neuroinflammation 14:49 |
