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 3

DLPFC HO-1 protein expression correlates with CSF and brain HIV RNA levels.

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DLPFC HO-1 protein expression correlates with CSF and brain HIV RNA leve...
Samples were derived from the HIV+ cohort for all subjects with detectable viral loads. Correlations were determined between DLPFC HO-1 protein expression, as determined by Western blot and densitometry analysis normalized to β-tubulin, and HIV RNA in (A) CSF, (B) brain parenchyma, and (C) plasma, and (D) plasma CD4 T lymphocyte count in HIV+ subjects. Associations were determined by multivariate linear regression with α = 0.01. Red regression lines denote significant trends.