HIV-associated neurocognitive disorders (HAND) remain prevalent despite the use of antiretroviral therapy (ART), and CNS inflammation &neurodegeneration associated with HIV replication in macrophages/microglia remain as neuropathological features. Persistent systemic inflammation &monocyte activation, CNS inflammation, macrophage activation, correlate with HAND in patients on ART. Thus, although ART is the backbone of HIV therapy, there is a critical need for adjunctive therapies to suppress persistent inflammation and virus replication, and to decrease the high burden of HAND- associated disability. Accordingly, drugs that suppress inflammation and HIV replication systemically and within the CNS are especially attractive as adjunctive neuroprotectants. We are proposing a dual-investigator MPI study (Kolson, Aldvoni) to investigate a novel drug, dimethyl fumarate, (DMF, Fumaderm(R)), now in a phase III clinical trial for multiple sclerosis) as a candidate neuroprotectant for HAND. Using our HIV neurotoxicity model we found that DMF and its primary in vivo metabolite, MMF, suppress a) HIV replication, b) associated inflammatory responses, and c) neurotoxin production in monocyte- derived macrophages (MDM). DMF/MMF also d) induces monocyte antioxidant responses and e) suppresses chemotaxis. In addition, using transcriptome analyses of HIV-infected T lymphocytes and MDM, we also demonstrated that HIV reprograms host gene expression in a cell-dependent manner to modulate pathways of virus spread, inflammatory mediators, and apoptosis, which can intersect pathways of HIV/MDM neurotoxin production &neurodegeneration. Because DMF is orally-deliverable, CNS- penetrating, and minimally toxic, we hypothesize that DMF can be an effective neuroprotectant in HAND and we further hypothesize that transcriptome analyses can identify host pathways modified by DMF/MMF that underlie its neuroprotection. We will: 1) Define mechanisms of DMF/MMF suppression of HIV replication and MDM neurotoxin production by HIV replication and Tat expression~ 2) Define DMF/MMF effects on suppression of monocyte & macrophage activation through anti-oxidant responses & other pathways~ 3) Determine mechanisms of DMF/MMF modulation of monocyte chemotaxis &transendothelial migration~ and 4) Determine the ability of DMF/MMF to suppress monocyte activation and induce antioxidant responses in SIV-infected rhesus macaques. This should provide a rationale for a future clinical trial in HIV patients.
Chronic inflammation persists in HIV-infected individuals despite systemic suppression of HIV replication by ART. Such inflammation can drive disease progression, both systemically and within the CNS. Dimethylfumarate (DMF) is a safe, effective anti- inflammatory drug (used in Europe to treat psoriasis) with CNS-protective, anti- inflammatory effects in multiple sclerosis patients. We will determine its potential neuroprotective use against HIV with investigations that should lead to a neuroprotection trial in HIV patients.
|Gannon, Patrick J; Akay-Espinoza, Cagla; Yee, Alan C et al. (2017) HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ?-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. Am J Pathol 187:91-109|
|Kovacsics, Colleen E; Gill, Alexander J; Ambegaokar, Surendra S et al. (2017) Degradation of heme oxygenase-1 by the immunoproteasome in astrocytes: A potential interferon-?-dependent mechanism contributing to HIV neuropathogenesis. Glia 65:1264-1277|
|McGuire, Jennifer L; Gill, Alexander J; Douglas, Steven D et al. (2016) The complement system, neuronal injury, and cognitive function in horizontally-acquired HIV-infected youth. J Neurovirol 22:823-830|
|McGuire, Jennifer L; Gill, Alexander J; Douglas, Steven D et al. (2015) Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders. J Neurovirol 21:439-48|
|Zyskind, Jacob W; Wang, Ying; Cho, Giyong et al. (2015) E2F1 in neurons is cleaved by calpain in an NMDA receptor-dependent manner in a model of HIV-induced neurotoxicity. J Neurochem 132:742-55|
|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|
|Ambegaokar, Surendra S; Kolson, Dennis L (2014) Heme oxygenase-1 dysregulation in the brain: implications for HIV-associated neurocognitive disorders. Curr HIV Res 12:174-88|
|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|
|Kukkonen, Sami; Martinez-Viedma, Maria Del Pilar; Kim, Nayoung et al. (2014) HIV-1 Tat second exon limits the extent of Tat-mediated modulation of interferon-stimulated genes in antigen presenting cells. Retrovirology 11:30|
Showing the most recent 10 out of 21 publications