Cited by 37Heme Oxygenase-1 and Carbon MonoxideHIV Research and TreatmentNeuroinflammation and Neurodegeneration Mechanisms

Heme oxygenase-1 promoter region (GT)n polymorphism associates with increased neuroimmune activation and risk for encephalitis in HIV infection

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Gill, Alexander J., Garza, Rolando, Ambegaokar, Surendra S., Gelman, Benjamin B., Kolson, Dennis L.·2018·Journal of Neuroinflammation

Abstract

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).”

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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)
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
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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