Regional Brain Recovery from Acute Synaptic Injury in Simian Immunodeficiency Virus-Infected Rhesus Macaques Associates with Heme Oxygenase Isoform Expression

• Type of Material: Article
• Authors: Yoelvis Garcia-Mesa, University of Pennsylvania; Rolando Garza, University of Pennsylvania; Maria E. Diaz Ortiz, University of Pennsylvania; Analise L. Gruenewald, University of Pennsylvania; Brandon L. Bastien, University of Pennsylvania; Rebecca Lobrovich, University of Pennsylvania; David J. Irwin, University of Pennsylvania; Michael R. Betts, University of Pennsylvania; Guido Silvestri, Emory University; Dennis L. Kolson, University of Pennsylvania
• Language: English
• Date: 2020-10-01
• Publisher: AMER SOC MICROBIOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Garcia-Mesa et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.01102-20
• Title of Journal or Parent Work: JOURNAL OF VIROLOGY
• Volume: 94
• Issue: 19
• Grant/Funding Information: This work was supported in part by National Institutes of Health R01 funding (MH104134 and MH111389 to D.L.K., R25 GM071745 to R.G., R56 Al106481 to M.R.B. and G.S., and OD P51OD011132 to the YNPRC).
• Keywords: HO-2; Virology; Science & Technology; OXIDATIVE STRESS; PATHOGENESIS; PROTECTION; Life Sciences & Biomedicine; I INTERFERON RESPONSES; brain; human immunodeficiency virus; DEFICIENCY; heme oxygenase; HO-1; MODEL; oxidative stress; SIV INFECTION; brainstem; simian immunodeficiency virus; POSTSYNAPTIC DENSITY; VULNERABILITY; MECHANISMS; neuroinflammation
• Research Categories: Biology, Virology; Biology, Neuroscience

Abstract

Brain injury occurs within days in simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) infection, and some recovery may occur within weeks. Inflammation and oxidative stress associate with such injury, but what drives recovery is unknown. Chronic HIV infection associates with reduced brain frontal cortex expression of the antioxidant/anti-inflammatory enzyme heme oxygenase-1 (HO-1) and increased neuroinflammation in individuals with cognitive impairment. We hypothesized that acute regional brain injury and recovery associate with differences in regional brain HO-1 expression. Using SIV-infected rhesus macaques, we analyzed multiple brain regions through acute and chronic infection (90 days postinfection [dpi]) and quantified viral (SIV gag RNA), synaptic (PSD-95; synaptophysin), axonal (neurofilament/neurofilament light chain [NFL]), inflammatory, and antioxidant (enzymes, including heme oxygenase isoforms [HO-1, HO-2]) markers. PSD-95 was reduced in the brainstem, basal ganglia, neocortex, and cerebellum within 13 dpi, indicating acute synaptic injury throughout the brain. All areas except the brainstem recovered. Unchanged NFL was consistent with no acute axonal injury. SIV RNA expression was highest in the brainstem throughout infection, and it associated with neuroinflammation. Surprisingly, during the synaptic injury and recovery phases, HO-2, and not HO-1, progressively decreased in the brainstem. Thus, acute SIV synaptic injury occurs throughout the brain, with spontaneous recovery in regions other than the brainstem. Within the brainstem, the high SIV load and inflammation, along with reduction of HO-2, may impair recovery. In other brain regions, stable HO-2 expression, with or without increasing HO-1, may promote recovery. Our data support roles for heme oxygenase isoforms in modulating recovery from synaptic injury in SIV infection and suggest their therapeutic targeting for promoting neuronal recovery. IMPORTANCE Brain injury induced by acute simian (or human) immunodeficiency virus infection may persist or spontaneously resolve in different brain regions. Identifying the host factor(s) that promotes spontaneous recovery from such injury may reveal targets for therapeutic drug strategies for promoting recovery from acute neuronal injury. The gradual recovery from such injury observed in many, but not all, brain regions in the rhesus macaque model is consistent with the possible existence of a therapeutic window of opportunity for intervening to promote recovery, even in those regions not showing spontaneous recovery. In persons living with human immunodeficiency virus infection, such neuroprotective treatments could ultimately be considered as adjuncts to the initiation of antiretroviral drug therapy.