HIV associated neurocognitive disorders (HAND) remain prevalent (~50%) despite remarkably improved patient survival due to improved antiretroviral therapy (ART) regimens. In HAND, CNS neuroinflammation & oxidative stress persist despite ART and continue to contribute to neuropathogenesis, which emphasizes the critical need for identifying host targets for adjunctive therapy for HAND prevention. We recently identified the cellular detoxifying/antioxidant enzyme, heme oxygenase-1 (HO-1), as such a target and we have demonstrated a significant deficiency of HO-1 expression in brain tissue from individuals with HAND. We also identified the recently FDA-approved CNS-penetrating multiple sclerosis drug (dimethyl fumarate/DMF/Tecfidera(R)), which stimulates HO-1 expression, as a unique candidate neuroprotectant for prevention of HAND. We propose to define the association between brain HIV-1 infection, HO-1 expression and HAND, and to establish a proof-of-concept therapeutic link to HO-1 induction as an adjunctive approach for HAND neuroprotection in a pilot dimethyl fumarate/DMF-treatment study of SIV-infected macques. Using our in vitro HIV neurodegeneration model we showed that HO-1 acts as a specific suppressor of HIV- induced neurodegeneration and that dimethyl fumarate/DMF induction of HO-1 is highly neuroprotective. Through analysis of autopsied brain tissue specimens (dorsolateral frontal cortex) from more than 150 HIV+ individuals, we found a significant deficiency of HO-1 expression and showed that this HO-1 deficiency correlates with neurocognitive (executive) dysfunction. Thus, HO-1 brain deficiency is directly linked with neurocognitive dysfunction in HIV-infected individuals, and a therapeutic approach that potentially can correct this deficiency and improve neurocognitive outcomes is at hand. We hypothesize that HIV-mediated suppression of brain HO-1 expression contributes to neuropathogenesis of HAND and that induction of HO-1 expression with dimethyl fumarate/DMF in ART-treated HIV+ individuals can limit the neuroinflammation, neurodegeneration and neurocognitive decline associated with HAND. We will determine: 1) correlations between regional brain HO-1 expression, immune activation, viral load, and neurocognitive performance in HIV+ individuals~ 2) mechanisms of HO-1 dysregulation by HIV~ and 3) whether DMF treatment alters HO-1 expression, neuroimmune activation, and neuropathogenesis of brain SIV infection in macaques.

Public Health Relevance

Neurocognitive dysfunction commonly arises in HIV-infected individuals despite systemic suppression of HIV replication by ART. Such dysfunction likely results from persistent inflammation and oxidative stress in the brain, and major component of the normal oxidative stress response is deficient in the brains of these individuals. A newly FDA-approved drug for multiple sclerosis, (Dimethylfumarate/DMF/Tecfidera(R)), that targets this deficiency could be an effective neuroprotectant against HIV-mediated neurocognitive dysfunction. We will determine how oxidative stress in the brain is linked to HIV neurocognitive dysfunction and conduct a pilot proof-of-principle neuroprotection trial of DMF in the simian immunodeficiency virus (SIV) primate model of HIV neuropathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH104134-01
Application #
8732299
Study Section
Special Emphasis Panel (ZRG1-AARR-E (03))
Program Officer
Colosi, Deborah
Project Start
2014-05-06
Project End
2019-04-30
Budget Start
2014-05-06
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$548,224
Indirect Cost
$139,924
Name
University of Pennsylvania
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Gill, Alexander J; Kovacsics, Colleen E; Vance, Patricia J et al. (2015) Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy. J Virol 89:10656-67
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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

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