HIV infection causes cognitive, motor, and behavioral deficits collectively known as HIV-associated neurocognitive disorders (HAND). Despite antiretroviral therapy, ~50% of HIV patients continue to develop neurocognitive impairment, affirming a need for adjunctive therapy. Clinical studies have shown that neurocognitive impairment in HAND correlates with CNS macrophage/microglia activation. Activated and HIV-infected monocyte-derived macrophages (HIV-MDM) and microglia mediate HAND neuropathology through soluble factors, including excitatory neurotoxins like glutamate, which induce neuronal injury. HAND patients have increased levels of glutamate in their CSF, which correlates with the degree of neurocognitive impairment and brain atrophy. Identification of endogenous pathways that regulate neurotoxin release, particularly glutamate, in HIV-MDM may provide important therapeutic targets for neurodegeneration in HAND. In vivo markers of oxidative stress correlate with neurocognitive impairment in HIV+ patients. We have specifically demonstrated that heme oxygenase-1 (HO-1), the sentinel cytoprotective antioxidant response protein, is a key regulator of HIV-MDM neurotoxicity. HO-1 is strikingly suppressed in HIV-MDM and correlates to glutamate production and neurotoxin release. In contrast, HO-1 induction in HIV-MDM decreases neurotoxin release, suggesting HO-1 as a novel therapeutic target in HAND. We found HO-1 expression to be decreased in the prefrontal cortex of HIV+ patients. This HO-1 suppression in the brain correlates with executive domain neurocognitive impairment, CNS viral load, and macrophage activation. We will evaluate the regional expression of HO-1 in an expanded panel of brain regions to determine correlations to relevant neurocognitive domains and markers of HIV disease progression. We will also investigate the currently unknown mechanism of HO-1 suppression in HIV-MDM through analysis of HO-1 mRNA and protein expression and stability. Lastly, we will expand upon our previous work to further define the therapeutic potential for HO-1 induction in reducing HIV-MDM neurotoxin production. Particularly, we will study the fumaric acid esters (FAEs), including dimethyl fumarate (DMF), as potential therapeutic candidates. DMF induces HO-1 through the ARE, cross the blood brain barrier, and has been shown to decrease neuroinflammation in multiple sclerosis phase III clinical trials. The safety and efficacy of DMF in MS trials, their anti-inflammatory properties, their induction of HO-1 underscore their therapeutic potential in HAND. We hypothesize that HIV-driven suppression of HO-1 in the CNS of HIV+ patients drives macrophage-mediated neurodegeneration and that reversal of this HO-1 deficiency through FAEs such as DMF will ameliorate this neurodegeneration.

Public Health Relevance

30-50% of HIV+ individuals, even those whose viral loads are adequately controlled with antiretroviral therapy, continue to suffer from HIV-associated neurocognitive disorders (HAND), highlighting a need for adjunctive therapy. We have shown that the brains of individuals with HAND are deficient in a critical cellular cytoprotective enzyme heme oxygenase-1 (HO-1) and we have demonstrated a role for HO-1 in suppressing HIV-mediated neuronal injury relevant to HAND. In particular, we are determining the potential of a class of novel drugs, the fumaric acid esters, as therapeutic inducers of HO-1 to serve as an adjunctive therapy in HAND patients.

National Institute of Health (NIH)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Stoff, David M
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University of Pennsylvania
Schools of Medicine
United States
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Gill, Alexander J; Kovacsics, Colleen E; Cross, Stephanie A et al. (2014) Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders. J Clin Invest 124:4459-72
Gill, Alexander J; Kolson, Dennis L (2014) Chronic inflammation and the role for cofactors (hepatitis C, drug abuse, antiretroviral drug toxicity, aging) in HAND persistence. Curr HIV/AIDS Rep 11:325-35
Chen, Maria F; Gill, Alexander J; Kolson, Dennis L (2014) Neuropathogenesis of HIV-associated neurocognitive disorders: roles for immune activation, HIV blipping and viral tropism. Curr Opin HIV AIDS 9:559-64