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Abstract
BackgroundHeme oxygenase-1 (HO-1) is a critical cytoprotective enzyme that limits oxidative stress, inflammation, and cellular injury within the central nervous system (CNS) and other tissues. We previously demonstrated that HO-1 protein expression is decreased within the brains of HIV+ subjects and that this HO-1 reduction correlates with CNS immune activation and neurocognitive dysfunction. To define a potential CNS protective role for HO-1 against HIV, we analyzed a well-characterized HIV autopsy cohort for two common HO-1 promoter region polymorphisms that are implicated in regulating HO-1 promoter transcriptional activity, a (GT)n dinucleotide repeat polymorphism and a single nucleotide polymorphism (A(-413)T). Shorter HO-1 (GT)n repeats and the ‘A’ SNP allele associate with higher HO-1 promoter activity.MethodsBrain dorsolateral prefrontal cortex tissue samples from an autopsy cohort of HIV−, HIV+, and HIV encephalitis (HIVE) subjects (n = 554) were analyzed as follows: HO-1 (GT)n polymorphism allele lengths were determined by PCR and capillary electrophoresis, A(-413)T SNP alleles were determined by PCR with allele specific probes, and RNA expression of selected neuroimmune markers was analyzed by quantitative PCR.ResultsHIV+ subjects with shorter HO-1 (GT)n alleles had a significantly lower risk of HIVE; however, shorter HO-1 (GT)n alleles did not correlate with CNS or peripheral viral loads. In HIV+ subjects without HIVE, shorter HO-1 (GT)n alleles associated significantly with lower expression of brain type I interferon response markers (MX1, ISG15, and IRF1) and T-lymphocyte activation markers (CD38 and GZMB). No significant correlations were found between the HO-1 (GT)n repeat length and brain expression of macrophage markers (CD163, CD68), endothelial markers (PECAM1, VWF), the T-lymphocyte marker CD8A, or the B-lymphocyte maker CD19. Finally, we found no significant associations between the A(-413)T SNP and HIVE diagnosis, HIV viral loads, or any neuroimmune markers.ConclusionOur data suggest that an individual’s HO-1 promoter region (GT)n polymorphism allele repeat length exerts unique modifying risk effects on HIV-induced CNS neuroinflammation and associated neuropathogenesis. Shorter HO-1 (GT)n alleles increase HO-1 promoter activity, which could provide neuroprotection through decreased neuroimmune activation. Therapeutic strategies that induce HO-1 expression could decrease HIV-associated CNS neuroinflammation and decrease the risk for development of HIV neurological disease.
Highlights
Heme oxygenase-1 (HO-1) is a critical cytoprotective enzyme that limits oxidative stress, inflammation, and cellular injury within the central nervous system (CNS) and other tissues
Several common genetic variations including (GT)n dinucleotide repeats and single nucleotide polymorphisms (SNPs) within the HO-1 promoter region modulate the level of promoter transcriptional activity, which suggests the likelihood of host variability in executing effective HO-1-driven protective responses to inflammation and cellular injury
We previously demonstrated that HO-1 protein expression is decreased in the brains of HIV-infected individuals diagnosed with HIV-associated neurocognitive disorders (HAND) and that this reduction of HO-1 is associated with CNS viral load and markers of neuroimmune activation, including type I interferon responses [2]
Summary
Heme oxygenase-1 (HO-1) is a critical cytoprotective enzyme that limits oxidative stress, inflammation, and cellular injury within the central nervous system (CNS) and other tissues. Heme oxygenase-1 (HO-1) is a sentinel, cytoprotective enzyme that has emerged as a critical effector for limiting oxidative stress, inflammation, and cellular injury within the central nervous system (CNS) and other tissues. Several common genetic variations including (GT)n dinucleotide repeats and single nucleotide polymorphisms (SNPs) within the HO-1 promoter region modulate the level of promoter transcriptional activity, which suggests the likelihood of host variability in executing effective HO-1-driven protective responses to inflammation and cellular injury. We previously demonstrated that HO-1 protein expression is decreased in the brains of HIV-infected individuals diagnosed with HIV-associated neurocognitive disorders (HAND) and that this reduction of HO-1 is associated with CNS viral load and markers of neuroimmune activation, including type I interferon responses [2]. We demonstrated that HIV infection of macrophages decreases macrophage HO-1 expression, but that this loss of HO-1 augments neurotoxin production from the infected macrophages [2, 5], suggesting that decreased HO-1 expression within the CNS may promote neuronal injury and dysfunction through enhanced neurotoxin production
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