Heme Oxygenase-1 as a novel therapeutic target in HIV-mediated neurodegeneration

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DESCRIPTION (provided by applicant): 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.