Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders.
Title | Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Gill, AJ, Kovacsics, CE, Cross, SA, Vance, PJ, Kolson, LL, Jordan-Sciutto, KL, Gelman, BB, Kolson, DL |
Journal | J Clin Invest |
Volume | 124 |
Issue | 10 |
Pagination | 4459-72 |
Date Published | 2014 Oct |
ISSN | 1558-8238 |
Keywords | Adult, Aged, Antioxidants, Astrocytes, Brain, Central Nervous System, Cognition Disorders, Cohort Studies, Dimethyl Fumarate, Female, Fumarates, Heme Oxygenase-1, HIV Infections, HIV-1, Humans, Inflammation, Internal, Linear Models, Macrophages, Male, Microglia, Middle Aged, Nervous System Diseases, Oxidative Stress, Prefrontal Cortex, RNA, Small Interfering, Virus Replication |
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. |
DOI | 10.1172/JCI72279 |
Alternate Journal | J Clin Invest |
PubMed ID | 25202977 |
PubMed Central ID | PMC4191052 |
Grant List | R01 NS056885 / NS / NINDS NIH HHS / United States F30 MH102120 / MH / NIMH NIH HHS / United States U01 MH083507 / MH / NIMH NIH HHS / United States U01 MH083500 / MH / NIMH NIH HHS / United States T32 AI007632 / AI / NIAID NIH HHS / United States MH083545 / MH / NIMH NIH HHS / United States AG000255 / AG / NIA NIH HHS / United States T32 AG000255 / AG / NIA NIH HHS / United States U24 MH100928 / MH / NIMH NIH HHS / United States MH104134 / MH / NIMH NIH HHS / United States R01 MH104134 / MH / NIMH NIH HHS / United States MH102120 / MH / NIMH NIH HHS / United States MH083501 / MH / NIMH NIH HHS / United States AI007632 / AI / NIAID NIH HHS / United States P51 OD011104 / OD / NIH HHS / United States R01 NS072005 / NS / NINDS NIH HHS / United States MH095671 / MH / NIMH NIH HHS / United States P30 AI045008 / AI / NIAID NIH HHS / United States MH083507 / MH / NIMH NIH HHS / United States NS043994 / NS / NINDS NIH HHS / United States R01 MH095671 / MH / NIMH NIH HHS / United States R01 MH083517 / MH / NIMH NIH HHS / United States U01 MH083501 / MH / NIMH NIH HHS / United States U01 MH083545 / MH / NIMH NIH HHS / United States U01 MH083506 / MH / NIMH NIH HHS / United States P30 MH092177 / MH / NIMH NIH HHS / United States NS072005 / NS / NINDS NIH HHS / United States U24 MH100930 / MH / NIMH NIH HHS / United States MH083506 / MH / NIMH NIH HHS / United States R01 NS043994 / NS / NINDS NIH HHS / United States MH083500 / MH / NIMH NIH HHS / United States |