Heme oxygenase-1 promoter (GT) _n polymorphism associates with HIV neurocognitive impairment

Abstract

ObjectiveTo determine whether regulatory variations in the heme oxygenase-1 (HO-1) promoter (GT)n dinucleotide repeat length could identify unique population genetic risks for neurocognitive impairment (NCI) in persons living with HIV (PLWH), we genotyped 528 neurocognitively assessed PLWH of European American and African American descent and linked genotypes to cognitive status.MethodsIn this cross-sectional study of PLWH (the CNS HIV Antiretroviral Therapy Effect Research cohort), we determined HO-1 (GT)n repeat lengths in 276 African Americans and 252 European Americans. Using validated criteria for HIV-associated NCI (HIV NCI), we found associations between allele length genotypes and HIV NCI and between genotypes and plasma markers of monocyte activation and inflammation. For comparison of HO-1 (GT)n allele frequencies with another population of African ancestry, we determined HO-1 (GT)n allele lengths in African PLWH from Botswana (n = 428).ResultsPLWH with short HO-1 (GT)n alleles had a lower risk for HIV NCI (OR = 0.63, 95% CI: 0.42–0.94). People of African ancestry had a lower prevalence of short alleles and higher prevalence of long alleles compared with European Americans, and in subgroup analyses, the protective effect of the short allele was observed in African Americans and not in European Americans.ConclusionsOur study identified the short HO-1 (GT)n allele as partially protective against developing HIV NCI. It further suggests that this clinical protective effect is particularly relevant in persons of African ancestry, where the lower prevalence of short HO-1 (GT)n alleles may limit induction of HO-1 expression in response to inflammation and oxidative stress. Therapeutic strategies that enhance HO-1 expression may decrease HIV-associated neuroinflammation and limit HIV NCI.

Neuroinflammation associates with antioxidant heme oxygenase-1 response throughout the brain in persons living with HIV

“…We concluded that HIV infection and HIV-driven neuroinflammation and immunoproteasome induction could lead to accelerated HO-1 protein degradation and loss, leading to neuronal injury and, ultimately, HIV-NCI. Finally, we also showed that the HO-1 gene promoter region (GT) n dinucleotide repeat genetic variation, which is known to modulate HO-1 transcriptional activity, associates with a risk of HIV-NCI and neuroinflammation in PLWH in a pattern consistent with a role for HO-1 in reducing risk of HIV-NCI (Garza et al 2020;Gill et al 2018). We thus hypothesized that PLWH have HIV-driven neuroinflammation and immunoproteasome expression throughout the brain that associates with HO-1 expression, and that this might associate with synaptic integrity in multiple regions, or even predominantly in selected regions.…”

“…We found significant associations between this polymorphism and type I IFN-stimulated genes and T lymphocyte activation within the prefrontal cortex of PLWH (Gill et al 2018). In a separate clinical cohort study of PLWH, we observed modulating effects of the HO-1 (GT) n promoter dinucleotide repeat on risk of HIV-NCI (Garza et al 2020). These observations suggest a balance between transcriptional and post-translational mechanisms of HO-1 modulation that determine parenchymal HO-1 levels in the setting of neuroinflammation in the prefrontal cortex, and they also suggest a role for HO-1 expression in modulating risk of HIV-NCI.…”

Heme oxygenase-1 modulation: A potential therapeutic target for COVID-19 and associated complications

“…With regard to the viral infections, recent data showed a lower risk of HIV-induced neuroencephalitis and neurocognitive impairment in patients with S allele [ 46 , 135 ]. Seu et al [ 136 ] reported high viral loads and soluble CD14 in HIV-infected patients on antiretroviral therapy having the L allele.…”

Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease

“…Specifically, longer (GT) n repeats are associated with low levels of HO-1 expression ( 21 ) and correlate with higher disease susceptibility, while shorter (GT) n repeats are associated with higher levels of HO-1 expression and correlate with lower disease susceptibility. This has been illustrated for cardiovascular disease ( 25 – 28 ), chronic kidney disease ( 29 , 30 ), HIV-induced central nervous system neuroinflammation ( 31 , 32 ), rheumatoid arthritis ( 33 ), chronic obstructive pulmonary disease ( 34 ), and organ transplantation ( 35 , 36 ). In sharp contrast, however, shorter (GT) n repeats are associated with higher levels of HO-1 expression and promote metaflammation associated with the onset of experimental metabolic disease ( 37 ).…”