{"id":{"repo_id":"penn","oai_identifier":"oai:repository.upenn.edu:20.500.14332/28579"},"canonical_url":"https://search.dev.ndltd.org/etd/penn/oai:repository.upenn.edu:20.500.14332/28579","repository":{"repo_id":"penn","name":"University of Pennsylvania","base_url":"https://repository.upenn.edu/server/oai/request"},"display":{"title":"A Novel Role for and Potential Therapeutic Targeting of Heme Oxygenase-1 in HIV Neuropathogenesis","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Gill, Alexander Julian"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Dennis L. Kolson"],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-01-01","date_published":"2015-01-01","updated_at":"2026-07-24T03:45:38Z","subjects":[],"languages":["en"],"rights":["Alexander Julian Gill"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://repository.upenn.edu/handle/20.500.14332/28579","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Dennis L. 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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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Doctor of Philosophy (PhD)"]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["A Novel Role for and Potential Therapeutic Targeting of Heme Oxygenase-1 in HIV Neuropathogenesis"]}]}],"canonical_facts":{"dc:contributor.advisor":["Dennis L. Kolson"],"dc:creator":["Gill, Alexander Julian"],"dc:date":["2023-05-17T15:57:17.000"],"dc:date.accessioned":["2023-05-22T16:46:07Z"],"dc:date.available":["2018-09-02T00:00:00Z"],"dc:date.issued":["2015-01-01"],"dc:description.abstract":["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."],"dc:description.degree":["Doctor of Philosophy (PhD)"],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://repository.upenn.edu/handle/20.500.14332/28579"],"dc:language":["en"],"dc:rights":["Alexander Julian Gill"],"dc:title":["A Novel Role for and Potential Therapeutic Targeting of Heme Oxygenase-1 in HIV Neuropathogenesis"],"dc:type":["Dissertation/Thesis"]},"updated_at":"2026-07-24T03:45:38Z"}