title: Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders.
abstract: Heme oxygenase-1 (HO-1) is an inducible, detoxifying enzyme that is critical for limiting oxidative stress, inflammation, and cellular injury within the CNS and other tissues. Here, we demonstrate a deficiency of HO-1 expression in the brains of HIV-infected individuals. This HO-1 deficiency correlated with cognitive dysfunction, HIV replication in the CNS, and neuroimmune activation. In vitro analysis of HO-1 expression in HIV-infected macrophages, a primary CNS HIV reservoir along with microglia, demonstrated a decrease in HO-1 as HIV replication increased. HO-1 deficiency correlated with increased culture supernatant glutamate and neurotoxicity, suggesting a link among HIV infection, macrophage HO-1 deficiency, and neurodegeneration. HO-1 siRNA knockdown and HO enzymatic inhibition in HIV-infected macrophages increased supernatant glutamate and neurotoxicity. In contrast, increasing HO-1 expression through siRNA derepression or with nonselective pharmacologic inducers, including the CNS-penetrating drug dimethyl fumarate (DMF), decreased supernatant glutamate and neurotoxicity. Furthermore, IFN-γ, which is increased in CNS HIV infection, reduced HO-1 expression in cultured human astrocytes and macrophages. These findings indicate that HO-1 is a protective host factor against HIV-mediated neurodegeneration and suggest that HO-1 deficiency contributes to this degeneration. Furthermore, these results suggest that HO-1 induction in the CNS of HIV-infected patients on antiretroviral therapy could potentially protect against neurodegeneration and associated cognitive dysfunction.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Gill
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Kovacsics
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Cross
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Vance
authors.forename: Lorraine L
authors.initials: LL
authors.lastname: Kolson
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Jordan-Sciutto
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Gelman
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kolson
mesh_terms: D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System; D003072:Cognition Disorders / Q000150:complications / Q000821:virology; D015331:Cohort Studies; D000069462:Dimethyl Fumarate; D005260:Female; D005650:Fumarates / Q000737:chemistry; D015658:HIV Infections / Q000378:metabolism / Q000503:physiopathology*; D015497:HIV-1; D051547:Heme Oxygenase-1 / Q000172:deficiency* / Q000502:physiology*; D006801:Humans; D007249:Inflammation; D016014:Linear Models; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D008297:Male; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009422:Nervous System Diseases / Q000378:metabolism / Q000503:physiopathology*; D018384:Oxidative Stress; D017397:Prefrontal Cortex / Q000473:pathology; D034741:RNA, Small Interfering / Q000378:metabolism; D014779:Virus Replication
chemical_list: D000975:Antioxidants; D005650:Fumarates; D034741:RNA, Small Interfering; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000069462:Dimethyl Fumarate