Despite a reduction in the incidence of HIV-associated dementia (HAD) in the era of Highly Active Anti-Retroviral Therapy (HAART), the prevalence of HAD is increasing, as is the frequency of minor cognitive diagnoses in HIV-positive patients. Although HAART is neurotoxic in both the peripheral nervous system and cultured neurons, the contribution of HAART to HIV-associated neurocognitive disorders is unknown. The toxicity of HAART compounds is due to distinct antiretroviral class-dependent mechanisms, such as alteration of protein metabolism and mitochondrial damage-induced generation of ROS (ROS), both of which have been implicated in other neurodegenerative conditions. These mechanisms, as well as HAART drugs themselves, can initiate the endoplasmic reticulum (ER) stress response, a multi-pronged pro-survival signaling pathway that may become deleterious if chronically activated, and autophagy, which has been implicated in neurodegeneration. An understanding of the cellular mechanisms triggered by the different classes of HAART drugs, in both neurons and macrophages, is crucial for guiding the design of new drugs and the assembly of combinational anti-retroviral therapies that minimize neurological impact. We hypothesize that HAART compounds induce neuronal toxicity both directly and indirectly (e.g. alteration of macrophage function), and that these mechanisms are mediated by cell-specific activation of stress responses that differ among classes of HAART compounds. Supporting this hypothesis, we have observed that individual antiretroviral drugs are neurotoxic in CNS cultures and that nontoxic drugs, when applied in recommended HAART combinations, become neurotoxic. We have also demonstrated an increase of downstream indicators of ER stress response activation in neurons and microglia/macrophages of patients with HIV-associated neurocognitive disorders, and in cultures of neurons and monocyte derived macrophages (MDM) following treatment with HAART compounds. Based on these findings, we propose to: 1) Determine the mechanisms of direct neuronal toxicity of HAART drug classes alone and in recommended, therapeutic combinations;2) Determine the mechanisms of direct toxicity of HAART drug classes (alone and in combination) in monocyte derived macrophages, 3) Determine the contributions of HAART-exposed MDM to neurotoxicity. By investigating the cell-specific mechanisms of HAART toxicity in the central nervous system we will uncover an unexplored source for cognitive impairment in HIV-positive patients, identify targets to mitigate side-effects of HAART compounds that effectively control viral replilcation, and create a model to detect neurotoxicity of current and future HAART compounds alone and in combination.
|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|
|Jensen, Brigid K; Monnerie, Hubert; Mannell, Maggie V et al. (2015) Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders. J Neuropathol Exp Neurol 74:1093-118|
|Ting, Jenhao H; Marks, David R; Schleidt, Stephanie S et al. (2014) Targeted gene mutation of E2F1 evokes age-dependent synaptic disruption and behavioral deficits. J Neurochem 129:850-63|
|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|
|Akay, Cagla; Cooper, Michael; Odeleye, Akinleye et al. (2014) Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol 20:39-53|
|Wang, Ying; Zyskind, Jacob W; Colacurcio, Daniel J et al. (2012) Differential roles for caspase-mediated and calpain-mediated cell death in 1- and 3-week-old rat cortical cultures. Neuroreport 23:1052-8|
|Akay, C; Lindl, K A; Shyam, N et al. (2012) Activation status of integrated stress response pathways in neurones and astrocytes of HIV-associated neurocognitive disorders (HAND) cortex. Neuropathol Appl Neurobiol 38:175-200|