HIV associated neurocognitive disorders (HAND) persist (~30% prevalence) worldwide in antiretroviral therapy (ART)-treated individuals despite a profound reduction in severe HAND (HIV-associated dementia/HAD). Biomarkers of oxidative stress in both systemic and CNS body compartments are strongly correlated with HAND, even in ART-treated individuals. Recently, we analyzed autopsied brains (>150 NNTC donors) and found a deficiency of a critical enzyme modulator of oxidative stress, heme oxygenase-1 (HO-1,) in those with HAND. This effect was independent of ART use and it correlated with brain macrophage activation and type I interferon responses. We further defined a link between brain HO-1 deficiency and HIV neuropathogenesis by showing that: i) HIV infection of monocyte-derived macrophages (MDM) consistently and selectively reduces HO-1 expression and increases neurotoxin (glutamate) release; ii) ART treatment of established HIV infection in MDM (HIV/MDM) does not prevent neurotoxin release, while iii) restoration of HO-1 expression in HIV/MDM does prevent neurotoxin release independent of ART and HIV replication. Our new preliminary studies also implicate dysregulation of brain HO-1 expression through a common HO-1 gene promoter sequence variation (GTn dinucleotide repeat length) and through regional variation in brain HO-1 expression in HAND pathogenesis. This HO-1 GTn dinucleotide repeat variation has previously been correlated with plasma markers of HIV disease progression (sCD14, HIV load) and our brain analyses demonstrate a strong correlation between HO-1 promoter GTn repeat length and the presence of HIV encephalitis. Additionally, our preliminary studies of autopsied rhesus macaque brains (n=18) demonstrated consistent regional (9 regions) brain differences in HO-1 expression levels, with lowest levels in deep brain structures where, in humans, HIV effects are particularly profound. Thus, our studies identify HIV-driven brain HO-1 deficiency as a major contributor to HAND pathogenesis, and they suggest that HO-1 promoter GTn repeat variation and brain regional HO-1 variation could be risk factors for HAND despite the use of ART. We hypothesize that HIV- induced brain HO-1 loss is a risk for HAND and that HO-1 promoter GTn repeat variation influences not only systemic HIV disease progression but also CNS disease progression and HAND. We further hypothesize that regional brain HO-1 levels contribute to selective regional vulnerability to HIV injury. We will: 1) Determine the correlation between HO-1 promoter GTn repeat variation and neurocognition in HIV+ subjects (CHARTER patient cohort); 2) Identify HO-1 variation associations with compartmental pathology and HIV disease markers (brain, spleen/NNTC autopsy cohort); and 3) Define the neuropathological in vitro responses of macrophages, astrocytes, endothelial cells relevant for blood-brain barrier function to HO-1 modulation and effects of the HO- 1 promoter GTn repeat variation on these responses. These studies can provide critical information for assessing cellular and clinical responses to HO-1-targeted therapies.
Kolson, Dennis L. Project Narrative: Neurocognitive dysfunction commonly arises in HIV-infected individuals despite systemic suppression of HIV replication by ART. Such dysfunction likely results from persistent inflammation and oxidative stress in the brain, and a major component of the normal oxidative stress response is deficient in the brains of these individuals. We have discovered a unique deficiency of a key anti-oxidative protein in the brains of individuals with HIV infection, and a link to neurocognitive dysfunction. We will determine how this protein is abnormally regulated in HIV infection through use of cell culture models and analysis of human tissue specimens from living and deceased individuals with HIV infection.
| Gill, Alexander J; Garza, Rolando; Ambegaokar, Surendra S et al. (2018) Heme oxygenase-1 promoter region (GT)n polymorphism associates with increased neuroimmune activation and risk for encephalitis in HIV infection. J Neuroinflammation 15:70 |
| Gelman, Benjamin B; Endsley, Janice; Kolson, Dennis (2018) When do models of NeuroAIDS faithfully imitate ""the real thing""? J Neurovirol 24:146-155 |
| Kovacsics, Colleen E; Gill, Alexander J; Ambegaokar, Surendra S et al. (2017) Degradation of heme oxygenase-1 by the immunoproteasome in astrocytes: A potential interferon-?-dependent mechanism contributing to HIV neuropathogenesis. Glia 65:1264-1277 |
