Heme Oxygenase-1 Dysregulation in the Brain: Implications for HIVAssociated Neurocognitive Disorders

Abstract

Heme oxygenase-1 (HO-1) is a highly inducible and ubiquitous cellular enzyme that subserves cytoprotective responses to toxic insults, including inflammation and oxidative stress. In neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, HO-1 expression is increased, presumably reflecting an endogenous neuroprotective response against ongoing cellular injury. In contrast, we have found that in human immunodeficiency virus (HIV) infection of the brain, which is also associated with inflammation, oxidative stress and neurodegeneration, HO-1 expression is decreased, likely reflecting a unique role for HO-1 deficiency in neurodegeneration pathways activated by HIV infection. We have also shown that HO-1 expression is significantly suppressed by HIV replication in cultured macrophages which represent the primary cellular reservoir for HIV in the brain. HO-1 deficiency is associated with release of neurotoxic levels of glutamate from both HIV-infected and immune-activated macrophages; this glutamate-mediated neurotoxicity is suppressed by pharmacological induction of HO-1 expression in the macrophages. Thus, HO-1 induction could be a therapeutic strategy for neuroprotection against HIV infection and other neuroinflammatory brain diseases. Here, we review various stimuli and signaling pathways regulating HO-1 expression in macrophages, which could promote neuronal survival through HO-1-modulation of endogenous antioxidant and immune modulatory pathways, thus limiting the oxidative stress that can promote HIV disease progression in the CNS. The use of pharmacological inducers of endogenous HO-1 expression as potential adjunctive neuroprotective therapeutics in HIV infection is also discussed.

Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy

“…Protective effects of HO-1 have been demonstrated in vitro and in vivo in animal models of oxidative, ischemic, and inflammatory diseases (8)(9)(10)(11). Our in vitro studies have identified HO-1 as a protective host factor against HIV-associated excitotoxic injury, and our analysis of autopsy brain specimens from a large cohort of HIV-infected decedents further demonstrated an association between brain HO-1 deficiency and cognitive impairment, thus suggesting a role for HO-1 deficiency in HIV neuropathogenesis (1). Because brain HO-1 deficiency is associated with cognitive impairment in HIV-infected individuals, we have proposed making HO-1 a therapeutic target for neuroprotection against HIV as an adjunctive therapy to antiretroviral therapy (ART) for preventing the pathogenic effects of HIV infection of the CNS (1,3).…”

“…Our in vitro studies have identified HO-1 as a protective host factor against HIV-associated excitotoxic injury, and our analysis of autopsy brain specimens from a large cohort of HIV-infected decedents further demonstrated an association between brain HO-1 deficiency and cognitive impairment, thus suggesting a role for HO-1 deficiency in HIV neuropathogenesis (1). Because brain HO-1 deficiency is associated with cognitive impairment in HIV-infected individuals, we have proposed making HO-1 a therapeutic target for neuroprotection against HIV as an adjunctive therapy to antiretroviral therapy (ART) for preventing the pathogenic effects of HIV infection of the CNS (1,3). HIV infection is associated with a syndrome of cognitive dysfunction (HIV-associated neurocognitive disorders [HAND]) in up to 50% of ART-treated HIV-infected individuals (12)(13)(14), which is thought to result in part from persistent inflammation and oxidative stress within both the CNS and systemic compartments (15).…”

“…eme oxygenase-1 (HO-1) is a highly inducible phase II detoxifying enzyme that has emerged as a critical effector for limiting cellular injury associated with oxidative stress and inflammation within the central nervous system (CNS) and other tissues in several disease states, including HIV infection (1)(2)(3). It is a member of a family of antioxidant response element (ARE) promoterdriven genes that are induced by the transcriptional regulator Nrf2 in response to a variety of cellular insults (4).…”

Pharmacological induction of hemeoxygenase-1 activity attenuates intracerebroventricular streptozotocin induced neurocognitive deficit and oxidative stress in rats

“…A long-term activity-dependent presynaptic enhancement during LTP, which is important in learning and memory, has also been found to be induced by CO (Barañano et al, 2002). Moreover, up-regulation of HO-1 activity has been reported to be beneficial in HIV-associated neurocognitive disorders (Ambegaokar and Kolson, 2014). The results of the present study and the earlier evidences suggest important role of HO-1 in cognitive disorders.…”

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

“…The potent antiinflammatory and cytoprotective actions of HO-1 have identified it as a potential therapeutic target in CNS inflammatory and neurodegenerative diseases (4,5). Among these diseases, HIV infection is associated with neurodegeneration that is thought to result from effects of persistent inflammation and oxidative stress in both systemic and CNS compartments that persist in individuals on antiretroviral therapy (ART) (6)(7)(8)(9).…”