Protection against early SIV brain injury with adjunctive therapy to cART

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Project Summary Prevention of HIV-associated neurocognitive impairment (HIV-NCI) remains elusive, despite the efficacy of cART in suppressing viral replication within the CNS. Although cART initiated immediately after HIV infection (INSIGHT START study) profoundly reduced disease progression, there was no neurocognitive advantage over delayed cART. Acute brain injury occurs within weeks of infection (HIV, SIV), before cART suppression is typically achieved. Spontaneous limited recovery may occur thereafter, suggesting a therapeutic window for rapid-acting neuroprotective treatments. These have not yet been tested. Our overall objective is to determine the ability of a rapidly-assimilated neuroprotective drug (dimethyl fumarate/DMF, FDA-approved), in combination with cART, to reduce injury and promote recovery in acute SIV infection in rhesus macaques. SIV/HIV injury is linked to oxidative stress and inflammation, which DMF can target through enhancing Nrf2- driven antioxidant enzyme expression and associated antioxidative/anti-inflammatory pathways. In our human brain autopsy studies, HIV-NCI associated with reduced expression of heme oxygenase-1 (HO-1), an antioxidant enzyme with two isoforms (HO-1 and -2), and with increased neuroinflammation. Moreover, HIV infection without HIV-NCI associated with increased HO-1 levels, consistent with a neuroprotective role for HO. In a separate cohort of persons living with HIV (PWH), we showed that an HO-1 promoter variation ((GT)n dinucleotide repeat)) that enhances HO-1 expression, associates with lower neuroinflammation and lower HIV- NCI risk. In acute HIV infection (in vitro) we showed that DMF induces HO-1 and other Nrf2 antioxidant enzymes in infected macrophages, and reduces TNF and glutamate release, thus linking enhanced enzyme expression with neuroprotection. In acute SIV infection in rhesus macaques, we defined a potential therapeutic window for DMF enhancement of antioxidant responses. We identified unique patterns of acute synaptic injury linked to low antioxidant enzyme levels, and changes in expression. Brainstem injury associated with higher neuroinflammation, lower enzyme levels, and progressive loss of HO-2. Recovery associated with stable HO-2 and increasing HO-1 levels. In our pilot macaque treatment study, DMF induced brain antioxidant enzymes, including HO-1, reduced oxidation of DNA and proteins, and produced a less-oxidized brain redox state. These findings support testing DMF as an adjunct to early cART. We hypothesize that DMF therapy concurrently with cART in acute SIV infection will reduce oxidative stress and acute neuronal injury while enhancing neuronal recovery throughout the brain. We will determine effects of concurrent DMF/cART on: (Aim 1) regional brain, oxidative injury, inflammation, neuronal integrity, signaling and recovery, and association with plasma markers of injury, oxidative stress and microbial translocation; (Aim 2) brain localization of immune cell infiltration, cell activation and oxidative injury in immune, endothelial, glial, and neuronal subtypes; and (Aim 3) infiltration of SIV-infected immune cells in brain and lymphatic tissue, in acute SIV infection of rhesus macaques.