Neuroinflammatory transcriptional programs induced in rhesus pre-frontal cortex white matter during acute SHIV infection
| Autor: | Chase E. Hawes, Sonny R. Elizaldi, Danielle Beckman, Giovanne B. Diniz, Yashavanth Shaan Lakshmanappa, Sean Ott, Blythe P. Durbin-Johnson, Ashok R. Dinasarapu, Andrea Gompers, John H. Morrison, Smita S. Iyer |
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| Rok vydání: | 2022 |
| Předmět: |
1.1 Normal biological development and functioning
Clinical Sciences Immunology Simian Acquired Immunodeficiency Syndrome T cells HIV Infections Neurodegenerative Basic Behavioral and Social Science Cellular and Molecular Neuroscience Neuro AIDS Neuroinflammation Underpinning research Rhesus macaque Behavioral and Social Science Genetics Acquired Cognitive Impairment Animals Humans 2.1 Biological and endogenous factors Viral Aetiology Neurology & Neurosurgery General Neuroscience Simian immunodeficiency virus Neurosciences Viral Load Macaca mulatta White Matter Frontal Lobe Brain Disorders Infectious Diseases Good Health and Well Being Neurology SHIV Neurological HIV-1 RNA Viral RNA HIV/AIDS Simian Immunodeficiency Virus RNA-seq Infection |
| Zdroj: | Journal of neuroinflammation, vol 19, iss 1 |
| Popis: | Background Immunosurveillance of the central nervous system (CNS) is vital to resolve infection and injury. However, immune activation within the CNS in the setting of chronic viral infections, such as HIV-1, is strongly linked to progressive neurodegeneration and cognitive decline. Establishment of HIV-1 in the CNS early following infection underscores the need to delineate features of acute CNS immune activation, as these early inflammatory events may mediate neurodegenerative processes. Here, we focused on elucidating molecular programs of neuroinflammation in brain regions based on vulnerability to neuroAIDS and/or neurocognitive decline. To this end, we assessed transcriptional profiles within the subcortical white matter of the pre-frontal cortex (PFCw), as well as synapse dense regions from hippocampus, superior temporal cortex, and caudate nucleus, in rhesus macaques following infection with Simian/Human Immunodeficiency Virus (SHIV.C.CH505). Methods We performed RNA extraction and sequenced RNA isolated from 3 mm brain punches. Viral RNA was quantified in the brain and cerebrospinal fluid by RT-qPCR assays targeting SIV Gag. Neuroinflammation was assessed by flow cytometry and multiplex ELISA assays. Results RNA sequencing and flow cytometry data demonstrated immune surveillance of the rhesus CNS by innate and adaptive immune cells during homeostasis. Following SHIV infection, viral entry and integration within multiple brain regions demonstrated vulnerabilities of key cognitive and motor function brain regions to HIV-1 during the acute phase of infection. SHIV-induced transcriptional alterations were concentrated to the PFCw and STS with upregulation of gene expression pathways controlling innate and T-cell inflammatory responses. Within the PFCw, gene modules regulating microglial activation and T cell differentiation were induced at 28 days post-SHIV infection, with evidence for stimulation of immune effector programs characteristic of neuroinflammation. Furthermore, enrichment of pathways regulating mitochondrial respiratory capacity, synapse assembly, and oxidative and endoplasmic reticulum stress were observed. These acute neuroinflammatory features were substantiated by increased influx of activated T cells into the CNS. Conclusions Our data show pervasive immune surveillance of the rhesus CNS at homeostasis and reveal perturbations of important immune, neuronal, and synaptic pathways within key anatomic regions controlling cognition and motor function during acute HIV infection. These findings provide a valuable framework to understand early molecular features of HIV associated neurodegeneration. |
| Databáze: | OpenAIRE |
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