Impact of HIV-1 TAT activation on retinal Müller glia: Implications for barrier properties.

HIV-associated immune activation is characterized by an increase in pro-inflammatory mediators and dysfunctional T-cells with senescent phenotypes. This persistent activation predisposes HIV-infected persons to non-AIDS-defining co-morbid conditions. At the retina, Müller glia undertake innate immune functions. Evidence from our microarray data shows changes in pathways which include cytokines, their receptors, and focal adhesion genes, suggesting inflammatory changes which could affect the blood-retinal barrier. Using a bioinformatics approach, we analyzed our dataset to identify changes in reactive Müller glia. Abnormalities in Müller glia signaling involve phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT). In silico analysis was validated by quantitative RT-PCR. PKB/AKT is increased in reactive Müller glia. Inhibition of PI3K/AKT affected transendothelial resistance in TAT-exposed Müller glia. Identification of a cluster of gene expression suggests underlying changes in the functions of Müller glia in maintaining barrier permeability through the PI3K/AKT signaling network. Activation of retinal Müller cells can therefore lead to proinflammatory molecular cascades that promote widespread physiological changes. Alterations in these pathways may affect vascular permeability, retinal and corneal angiogenesis, and disruption of the blood-ocular barrier.