Date of Award
Doctor of Philosophy (PhD)
Dennis L. Kolson
HIV-associated neurocognitive disorders (HAND) affect up to 50% of HIV-infected adults despite potent viral suppression with antiretroviral therapy (ART) and are associated with persistent neuronal damage, monocyte/macrophage activation, chronic inflammation, and oxidative stress. Heme oxygenase-1 (HO-1) is a highly inducible, detoxifying enzyme critical for limiting oxidative stress, inflammation, and cellular injury within the central nervous system (CNS) and other tissues. Our analysis of HO-1 expression in the brain prefrontal cortex from HIV-infected individuals demonstrated a significant HO-1 protein deficiency, even in HIV-infected subjects treated with ART. This HO-1 deficiency associated with a diagnosis of HAND and HIV-encephalitis (HIVE) as well as with elevated CNS HIV replication, type I interferon responses, and macrophage activation. Within this cohort longer variants of a HO-1 promoter region (GT)n microsatellite polymorphism, which cause reduced HO-1 gene expression, associated with increased risk of HIVE and elevated CNS macrophage activation. HIV replication in macrophages, a primary CNS HIV reservoir, selectively reduced HO-1 protein and RNA expression and induced production of neurotoxic levels of glutamate. This HO-1 deficiency and associated neurotoxin production was a conserved feature of infection with macrophage-tropic HIV-1 and HIV-2 strains that correlated closely with the extent of replication. ART regimens applied to macrophages after HIV infection was established failed to prevent this HO-1 loss and associated neurotoxin production. HO-1 siRNA knockdown and enzymatic inhibition in HIV-infected macrophages increased supernatant glutamate and neurotoxicity. In contrast, increasing HO-1 expression through siRNA derepression or with pharmacologic inducers, including the CNS-penetrating drug dimethyl fumarate (DMF), decreased supernatant glutamate and neurotoxicity. These findings identify HO-1 as a host factor that is deficient in the brains of HIV-infected individuals and suggest that loss of HO-1 and its protective functions may contribute to HIV neuropathogenesis. Moreover, this work defines a predictable and conserved relationship between HIV replication, HO-1 loss, and neurotoxin production in macrophages that likely reflects processes in place in the HIV-infected brain of individuals receiving ART. Correcting this HO-1 deficiency could provide a novel approach for neuroprotection in individuals with or at risk for developing HAND above that provided by current ART.
Gill, Alexander Julian, "A Novel Role for and Potential Therapeutic Targeting of Heme Oxygenase-1 in HIV Neuropathogenesis" (2015). Publicly Accessible Penn Dissertations. 1736.
Available for download on Sunday, September 02, 2018