Define the correlations between brain heme oxygenase-1, endothelial activation, and neuronal injury in HIV infection.

In HIV infection, blood-brain barrier damage in the basal ganglia correlates with cognitive impairment, suggesting vulnerability linked to endothelial dysfunction. We identified reduced pre-frontal cortex expression of heme oxygenase-1/HO-1 (antioxidant enzyme), as a cognitive dysfunction risk; we also identified brain HO-1 variation in SIV-infected macaques, which correlated with neuronal injury. We now hypothesize that human brain HO-1 expression varies regionally and correlates with endothelial adhesion markers and neuronal injury in HIV.

Brain HO-1 RNA varies regionally, and, in HIV+ subjects, correlates with endothelial molecules (ICAM-1, p<0.05; VCAM, p<.01; PECAM, p<.001) and post-synaptic neuronal integrity (PSD95, p<.0001; synaptophysin, ns) in cortical regions, but not basal ganglia. Additionally, within HIV+ subjects: i)HO-1 RNA is higher (p<.05), and PSD95 is lower (p<0.0001) in basal ganglia vs. cortical regions, consistent with our macaque findings; ii)endothelial adhesion molecules are higher in basal ganglia vs. cortical regions (ICAM-1 p<0.01, VCAM p<0.01, PECAM, ns); and iii)PSD95 is lower in basal ganglia, but not cortical regions, in HIV+ vs HIV- subjects (p<.01). 

Regional brain variation in the anti-oxidant response (HO-1) is linked to post-synaptic neuronal injury and increased endothelial adhesion markers. This suggests greater vulnerability of basal ganglia (vs cortical regions) to HIV-mediated injury, possibly through increased drive for transendothelial immune cell migration, which may be regionally regulated by HO-1.