Heme oxygenase-1 promoter region (GT)n polymorphism associates with increased neuroimmune activation and risk for encephalitis in HIV infection
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BACKGROUND: 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. 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. METHODS: Brain 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. RESULTS: HIV+ 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. CONCLUSION: Our 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.
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Shorter HO-1 (GT)n alleles improve acute kidney injury and outcome after kidney transplantation in mouse models, at least partly due to increased HO-1 promoter activity.
“Shorter HO-1 (GT)n alleles have been found to improve acute kidney injury and outcome after kidney transplantation in mouse models (Leaf et al. 2016), at least partly due to the increase in HO-1 promoter activity (Gill et al. 2018).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Gill et al. 2018
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- Authors
- Gill, A. J., Garza, R., Ambegaokar, S. S., Gelman, B. B., & Kolson, D. L.
- Affiliations
- University of Pennsylvania (US)
- Ohio Wesleyan University (US)
- The University of Texas Medical Branch at Galveston (US)
- Corresponding author
- Kolson, Dennis L.
- Venue
- Journal of Neuroinflammation
- Published
- 2018-03-06
- Volume
- 15
- Issue
- 1
- Pages
- 70-70
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC5838989
- OpenAlex
- W2802982213
- Cited by
- 37
- References
- 73
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 8 · 2021: 5 · 2020: 7 · 2019: 1 · 2018: 1
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Mental Health (R01MH095671, R01MH104134, R01MH101017, F30MH102120)
- National Institute of Neurological Disorders and Stroke (T32NS007180)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- heme oxygenase-1, HIV-associated neurocognitive disorders, HIV encephalitis, neuroinflammation, neuroimmune activation, type I interferon response, T cell activation, genetic susceptibility, prefrontal cortex, oxidative stress
- MeSH terms
- Adult, Aged, Brain, Female, Humans, Male, Middle Aged, Polymorphism, Genetic, Promoter Regions, Genetic, RNA, Messenger, Cohort Studies, HIV Infections, Antigens, CD, Encephalitis, Viral, Dinucleotide Repeats, Heme Oxygenase-1, Genetic Association Studies
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