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

Abstract

Brain injury occurs within days in SIV or 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 dpi), and quantified markers: viral (SIV gag RNA), synaptic (PSD-95, synaptophysin), axonal (neurofilament/NFL), inflammatory, and antioxidant (enzymes, including heme oxygenase isoforms [HO-1, HO-2]). PSD-95 was reduced in brainstem, basal ganglia, neocortex, and cerebellum within 13 dpi, indicating acute synaptic injury throughout the brain. All areas except brainstem recovered. Unchanged NFL is consistent with no acute axonal injury. SIV RNA expression was highest in brainstem throughout infection, and it associated with neuroinflammation. Surprisingly, during synaptic injury and recovery phases, HO-2, and not HO-1, progressively decreased in brainstem. Thus, acute SIV synaptic injury occurs throughout the brain, with spontaneous recovery in regions other than 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 promote spontaneous recovery from such injury may reveal targets for therapeutic drug strategies for promoting recovery from acute neuronal injury. The gradual recovery from the injury observed in many, but not all, brain regions in the rhesus macaque model is consistent with there being a possible 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 initiation of antiretroviral drug therapy.

Dimethyl Fumarate, an Approved Multiple Sclerosis Treatment, Reduces Brain Oxidative Stress in SIV-Infected Rhesus Macaques: Potential Therapeutic Repurposing for HIV Neuroprotection

“…The persistent risk for brain injury and associated neurocognitive impairment in persons living with HIV, despite the suppression of virus replication with antiretroviral therapy, underscores the need for the identification of adjunctive neuroprotective strategies [ 66 , 67 ]. Abundant evidence, including data from our studies, suggests that oxidative stress and neuroinflammation contribute to the risk for brain injury in acute and chronic HIV and SIV infections [ 4 , 6 , 20 , 68 , 69 , 70 , 71 ]. To address the need for identifying an effective adjunctive neuroprotection strategy, we examined the ability of DMF—an FDA-approved, anti-oxidative, and anti-inflammatory drug—to limit brain oxidative stress and neuroinflammation in chronically SIV-infected rhesus macaques, which is the non-human primate model of HIV infection.…”

“…We, therefore, have suggested the potential safe use of DMF in persons living with HIV as an adjunctive neuroprotective therapy [ 34 ]. Whether DMF prevents neuronal injury in SIV-infected macaques remains to be determined, where this is a future goal for testing DMF effects on early brain injury in SIV infection in immune-competent macaques as a model for neuroprotection in acute HIV infection [ 6 ].…”

“…The plasma and CSF collected from each animal at its necropsy time point were used to quantify NFL using a Singleplex Assay (Meso Scale Discovery, Rockville, MD, USA), as described in the R-PLEX™ protocol and as previously reported [ 6 ].…”

“…Despite the effectiveness of combination antiretroviral therapy (cART) in suppressing human immunodeficiency virus (HIV) replication in the peripheral and central nervous system (CNS) compartments, individuals remain at risk for secondary complications that are related to persistent or recurrent inflammation and oxidative stress in all compartments [ 1 , 2 , 3 , 4 , 5 ]. In the rhesus macaque simian immunodeficiency virus (SIV) infection model and in persons living with HIV, early and persistent damage to the brain and other tissues are observed [ 2 , 3 , 6 , 7 ]. Damage to gut-associated lymphoid tissue results in acute and chronic immune activation, inflammation, and oxidative stress.…”

Advances in SIV/SHIV Non-Human Primate Models of NeuroAIDS

“…Despite ART therapy, secondary complications of the CNS compartment remain at risk in HIV-1-infected individuals [ 109 , 110 ] due to persistent immune activation within the CNS, and to the release of pro-inflammatory cytokines, chemokines, reactive oxygen metabolites, and viral proteins, which ultimately leads to neurodegeneration [ 110 , 111 ]. Oxidative stress and chronic inflammation may contribute to brain injury in acute and chronic SIV infections [ 111 , 112 ]. Thus, protective therapies that aim at suppressing these pathologic pathways would be desirable.…”