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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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 5

HIV infection of MDM reduces HO-1 protein expression and concomitantly increases supernatant glutamate levels and neurotoxicity.

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HIV infection of MDM reduces HO-1 protein expression and concomitantly i...
Infected (HIV-MDM) and mock-infected cultures (mock-MDM) were sampled and harvested every 3 days post infection (DPI) for analysis of supernatant glutamate content, supernatant neurotoxicity, and cellular protein expression. (A) Mean supernatant RT activity from representative HIV-infected cultures. (B) Western blot of selected ARE proteins (NQO1, HO-1, and GPX1) over the 15-day course of representative HIV-MDM infections. (C) Quantification of expression of canonical ARE proteins and HO-2 over the course of infection, as determined by Western blotting. Values represent mean ± SEM (n = 4 different macrophage donor cultures) of the fold change in protein expression in HIV-infected versus mock-infected MDM. (D) Supernatant glutamate concentration and (E) supernatant neurotoxicity as measured by MAP2 expression in supernatant-exposed rat primary neuronal cultures) normalized to untreated (UT). RT, glutamate, and neurotoxicity data are representative of 4 independent experiments, with each replicate performed on MDM preparations from different donors. (F) Quantification of MDM cell death at 12 days after HIV infection. Results are averaged from 3 independent donors. Camptothecin (CT, 6 hour exposure) and complete cell lysis (max, maximum cytotoxicity) served as positive controls. All values represent mean ± SEM. Statistical comparisons were made by paired Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.