Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders
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
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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Research Article AIDS/HIV

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 7

Exposure of HIV-MDM to an inhibitor of heme oxygenase enzymatic activity (SnMP) enhances glutamate release and supernatant neurotoxicity independently of HIV replication.

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Exposure of HIV-MDM to an inhibitor of heme oxygenase enzymatic activity...
SnMP, an inhibitor of heme oxygenase activity, was added to HIV-MDM cultures on days 6, 9, and 12 post infection. (A) HIV replication (supernatant RT activity). (B) Western blot of cell lysates (day 15) for detection of ARE proteins HO-1, NQO1, and GPX1. (C) Supernatant (day 12) glutamate concentration and (D) supernatant neurotoxicity. (E) Supernatant (day 15) glutamate concentration and (F) supernatant neurotoxicity. Values represent mean ± SEM of technical replicates from a representative experiment of 3 independent experiments, with each biological replicate performed on MDM preparations from a different donor. Statistical comparisons were made by 1-way ANOVA plus Hold-Sidak post hoc test. ***P < 0.001.