Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders
Alexander J. Gill, … , Benjamin B. Gelman, Dennis L. Kolson
Alexander J. Gill, … , Benjamin B. Gelman, Dennis L. Kolson
Published September 9, 2014
Citation Information: J Clin Invest. 2014;124(10):4459-4472. https://doi.org/10.1172/JCI72279.
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Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders

Abstract

Heme oxygenase-1 (HO-1) is an inducible, detoxifying enzyme that is critical for limiting oxidative stress, inflammation, and cellular injury within the CNS and other tissues. Here, we demonstrate a deficiency of HO-1 expression in the brains of HIV-infected individuals. This HO-1 deficiency correlated with cognitive dysfunction, HIV replication in the CNS, and neuroimmune activation. In vitro analysis of HO-1 expression in HIV-infected macrophages, a primary CNS HIV reservoir along with microglia, demonstrated a decrease in HO-1 as HIV replication increased. HO-1 deficiency correlated with increased culture supernatant glutamate and neurotoxicity, suggesting a link among HIV infection, macrophage HO-1 deficiency, and neurodegeneration. HO-1 siRNA knockdown and HO enzymatic inhibition in HIV-infected macrophages increased supernatant glutamate and neurotoxicity. In contrast, increasing HO-1 expression through siRNA derepression or with nonselective pharmacologic inducers, including the CNS-penetrating drug dimethyl fumarate (DMF), decreased supernatant glutamate and neurotoxicity. Furthermore, IFN-γ, which is increased in CNS HIV infection, reduced HO-1 expression in cultured human astrocytes and macrophages. These findings indicate that HO-1 is a protective host factor against HIV-mediated neurodegeneration and suggest that HO-1 deficiency contributes to this degeneration. Furthermore, these results suggest that HO-1 induction in the CNS of HIV-infected patients on antiretroviral therapy could potentially protect against neurodegeneration and associated cognitive dysfunction.

Authors

Alexander J. Gill, Colleen E. Kovacsics, Stephanie A. Cross, Patricia J. Vance, Lorraine L. Kolson, Kelly L. Jordan-Sciutto, Benjamin B. Gelman, Dennis L. Kolson

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Figure 9

DMF and MMF reduce glutamate release and associated supernatant neurotoxicity in HIV-MDM independently of HIV replication.

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DMF and MMF reduce glutamate release and associated supernatant neurotox...
DMF and MMF were added to HIV-MDM on day 6 post infection and replenished on day 9 post infection. tBHQ was added on day 9 post infection and not replenished. Culture supernatants (day 12 post infection) were assayed for glutamate concentration and neurotoxicity normalized to untreated primary rat neuronal cultures (UT). (A) HIV replication (supernatant RT activity), (B) supernatant glutamate concentration, and (C) supernatant neurotoxicity in DMF-treated HIV-MDM. Similar effects of DMF treatment in HIV-MDM were observed in 4 of 5 independent experiments, with each replicate performed on MDM preparations from a different donor. (D) HIV replication (supernatant RT activity), (E) supernatant glutamate concentration, and (F) supernatant neurotoxicity in MMF-treated HIV-MDM. Similar effects of MMF treatment in HIV-MDM were observed in 3 of 4 independent experiments, with each replicate performed on MDM preparations from a different donor. (G) HIV replication (supernatant RT activity), (H) supernatant glutamate concentration, and (I) supernatant neurotoxicity in tBHQ-treated HIV-MDM. Similar effects of tBHQ treatment in HIV-MDM were observed in 3 of 3 independent experiments, with each replicate performed on MDM preparations from a different donor. Values represent mean ± SEM. Statistical comparisons were made by 1-way ANOVA plus Hold-Sidak post hoc test. Veh, vehicle. *P < 0.05; **P < 0.01; ***P < 0.001 versus vehicle.