Heme oxygenase-1 promoter region (GT)n polymorphism associates with increased neuroimmune activation and risk for encephalitis in HIV infection.
Title | Heme oxygenase-1 promoter region (GT)n polymorphism associates with increased neuroimmune activation and risk for encephalitis in HIV infection. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Gill, AJ, Garza, R, Ambegaokar, SS, Gelman, BB, Kolson, DL |
Journal | J Neuroinflammation |
Volume | 15 |
Issue | 1 |
Pagination | 70 |
Date Published | 2018 Mar 06 |
ISSN | 1742-2094 |
Keywords | Adult, Aged, Antigens, CD, Brain, Cohort Studies, Dinucleotide Repeats, Encephalitis, Viral, Female, Genetic Association Studies, Heme Oxygenase-1, HIV Infections, Humans, Male, Middle Aged, Polymorphism, Genetic, Promoter Regions, Genetic, RNA, Messenger |
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 (nā=ā554) 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. |
DOI | 10.1186/s12974-018-1102-z |
Alternate Journal | J Neuroinflammation |
PubMed ID | 29510721 |
PubMed Central ID | PMC5838989 |
Grant List | F30 MH102120 / MH / NIMH NIH HHS / United States U24 MH100929 / MH / NIMH NIH HHS / United States R01MH095671 / / National Institute of Mental Health / R01MH104134 / / National Institute of Mental Health / T32 NS007180 / NS / NINDS NIH HHS / United States F30MH102120 / / National Institute of Mental Health / R01 MH104134 / MH / NIMH NIH HHS / United States R01MH101017 / / National Institute of Mental Health / U24 MH100930 / MH / NIMH NIH HHS / United States R01 MH111389 / MH / NIMH NIH HHS / United States T32NS007180 / / National Institute of Neurological Disorders and Stroke / |