Abstract
Cognitive dysfunction persists in 30–50% of chronically HIV-infected individuals despite combination antiretroviral therapy (ART). Although monocytes are implicated in poor cognitive performance, distinct biological mechanisms associated with cognitive dysfunction in HIV infection are unclear. We previously showed that a regulatory region of the interferon regulatory factor-8 (IRF8) gene is hyper-methylated in HIV-infected individuals with cognitive impairment compared to those with normal cognition. Here, we investigated IRF-8 protein expression and assessed relationships with multiple parameters associated with brain health. Intracellular IRF-8 expression was measured in cryopreserved peripheral blood mononuclear cells from chronically HIV-infected individuals on ART using flow cytometry. Neuropsychological performance was assessed by generating domain-specific standardized (NPZ) scores, with a global score defined by aggregating individual domain scores. Regional brain volumes were obtained by magnetic resonance imaging and soluble inflammatory factors were assessed by immunosorbent assays. Non-parametric analyses were conducted and statistical significance was defined as p < 0.05. Twenty aviremic (HIV RNA<50 copies/ml) participants, 84% male, median age 51 [interquartile range (IQR) 46, 55], median CD4 count 548 [439, 700] were evaluated. IRF-8 expression was highest in plasmacytoid dendritic cells (pDCs). Assessing cognitive function, lower IRF-8 density in classical monocytes significantly correlated with worse NPZ_learning memory (LM; rho = 0.556) and NPZ_working memory (WM; rho = 0.612) scores, in intermediate monocytes with worse NPZ_LM (rho = 0.532) scores, and in non-classical monocytes, lower IRF-8 correlated with worse global NPZ (rho = 0.646), NPZ_LM (rho = 0.536), NPZ_WM (rho = 0.647), and NPZ_executive function (rho = 0.605) scores. In myeloid DCs (mDCs) lower IRF-8 correlated with worse NPZ_WM (rho = 0.48) scores and in pDCs with worse NPZ_WM (rho = 0.561) scores. Declines in IRF-8 in classical monocytes significantly correlated with smaller hippocampal volume (rho = 0.573) and in intermediate and non-classical monocytes with smaller cerebral white matter volume (rho = 0.509 and rho = 0.473, respectively). IRF-8 density in DCs did not significantly correlate with brain volumes. Among biomarkers tested, higher soluble ICAM-1 levels significantly correlated with higher IRF-8 in all monocyte and DC subsets. These data may implicate IRF-8 as a novel transcription factor in the neuropathophysiology of brain abnormalities in treated HIV and serve as a potential therapeutic target to decrease the burden of cognitive dysfunction in this population.
Highlights
Cognitive performance is compromised in ∼30–50% of chronically HIV-infected individuals despite access to combination antiretroviral therapy (ART) [1, 2]
Among the myeloid subsets analyzed, plasmacytoid dendritic cells (DCs) had the highest interferon regulatory factor-8 (IRF-8) expression (geometric mean fluorescence intensity (GMF) 1501 [1273, 1651]), which was significantly higher than all 3 monocyte subsets and myeloid DCs (GMF 250 [222,277]) in concordance with a previous murine study (p’s
Given our intriguing methylation data demonstrating a link between the IRF8 gene and HIV-associated cognitive impairment, the protein expression of intracellular IRF-8 was investigated in peripheral myeloid cells in virally suppressed HIV-infected individuals with multi-dimensional measures of cognitive performance and brain volumes
Summary
Cognitive performance is compromised in ∼30–50% of chronically HIV-infected individuals despite access to combination antiretroviral therapy (ART) [1, 2] These cognitive, behavioral, and motor deficits are widespread, and impact everyday functioning, increase morbidity and mortality and have lasting critical public health effects [3,4,5]. Since clinically approved therapies for HIV-associated cognitive impairment are not available [6], there is need to identify novel therapeutic targets The transmigration of both infected and uninfected monocytes into the central nervous system (CNS) is thought to be a significant mediator of the development of cognitive disorders during HIV infection, primarily by promoting viral seeding of CNS resident cells and promoting neuroinflammatory responses [7,8,9,10,11,12,13,14]. A better understanding of molecular mechanisms linking peripheral myeloid cells to the CNS is crucial to further elucidate the pathophysiology of HIV-associated brain injury
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