Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders

J Clin Invest. 2014 Oct;124(10):4459-72. doi: 10.1172/JCI72279. Epub 2014 Sep 9.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Antioxidants / metabolism
  • Astrocytes / metabolism
  • Brain / metabolism
  • Central Nervous System
  • Cognition Disorders / complications
  • Cognition Disorders / virology
  • Cohort Studies
  • Dimethyl Fumarate
  • Female
  • Fumarates / chemistry
  • HIV Infections / metabolism
  • HIV Infections / physiopathology*
  • HIV-1
  • Heme Oxygenase-1 / deficiency*
  • Heme Oxygenase-1 / physiology*
  • Humans
  • Inflammation
  • Linear Models
  • Macrophages / metabolism
  • Macrophages / virology
  • Male
  • Microglia / metabolism
  • Middle Aged
  • Nervous System Diseases / metabolism
  • Nervous System Diseases / physiopathology*
  • Oxidative Stress
  • Prefrontal Cortex / pathology
  • RNA, Small Interfering / metabolism
  • Virus Replication


  • Antioxidants
  • Fumarates
  • RNA, Small Interfering
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • Dimethyl Fumarate