Occludin modulates HIV and ischaemic stroke response via mitochondrial antiviral signalling pathway

Abstract Specific cell types of the blood-brain barrier (BBB), such as pericytes, can be infected by HIV-1. Importantly, alterations of the expression of tight junction protein occludin have been linked to regulation of HIV-1 infection. In the present study, we hypothesized that occludin can influence HIV-1 infection via modulating innate immunity responses. Unbiased transcriptome analysis was conducted on wild type and occludin-silenced primary human blood-brain barrier pericytes. The role of differentially expressed innate-immunity pathways was then evaluated in the context of mitochondrial dysfunction and HIV-1 infection. Using a model of ischemic stroke and occludin-deficient mice, we elucidated the functional role of occludin in cerebrovascular health in the presence of HIV-1 infection. Occludin silencing resulted in alterations of the gene expression signatures of IFN-stimulated genes and the antiviral retinoic acid-inducible gene-1 pathway, which functions as a regulator of the cytoplasmic sensors upstream of the mitochondrial antiviral signaling protein. Indeed, we observed dysfunctional mitochondrial bioenergetics, dynamics, and autophagy following occludin silencing. Alterations of mitochondrial bioenergetics and innate immune protection translated into worsened ischemic stroke outcomes in EcoHIV-infected occludin-deficient mice. Animal studies also confirmed that occludin-/- mice had higher EcoHIV load in plasma, spleen, and brain. Our results allow for a better understanding of the molecular mechanisms of viral infection in the brain and describe a previously unrecognized role of occludin as a key factor in the control of innate immune responses and mitochondrial dynamics at the blood-brain barrier level, which influence cerebral vascular disease outcomes such as ischemic stroke.