Combination of HIV-1 and Diabetes Enhances Blood Brain Barrier Injury via Effects on Brain Endothelium and Pericytes.

Despite combined antiretroviral therapy (ART) achieving efficient HIV replication control, HIV-associated neurocognitive disorders (HAND) continue to be highly prevalent in HIV-infected patients. Diabetes mellitus (DM) is a well-known comorbidity of HAND in HIV-infected patients. Blood brain barrier (BBB) dysfunction has been linked recently to dementia development, specifically in DM patients. BBB injury exists both in HIV and DM, likely contributing to cognitive decline. However, its extent, exact cellular targets and mechanisms are largely unknown. In this report, we found a decrease in pericyte coverage and expression of tight junction proteins in human brain tissues from HIV patients with DM and evidence of HAND when compared to HIV-infected patients without DM or seronegative DM patients. Using our in vitro BBB models, we demonstrated diminution of barrier integrity, enhanced monocyte adhesion, changes in cytoskeleton and overexpression of adhesion molecules in primary human brain endothelial cells or human brain pericytes after exposure to HIV and DM-relevant stimuli. Our study demonstrates for the first-time evidence of impaired BBB function in HIV-DM patients and shows potential mechanisms leading to it in brain endothelium and pericytes that may result in poorer cognitive performance compared to individuals without HIV and DM.

Reduction in phosphorylated heavy neurofilament in the cerebellum in HIV disease.

In the absence of significant neuronal infection HIV induces neuronal damage and death. The pathogenesis of this process is not clear and can only be assessed in the HIV infected brain by examining surviving neuronal populations. Cerebellar Purkinje cells are a model population. We have already demonstrated glutamate receptor alterations in these neurons in AIDS, and in the current study we have investigated the phosphorylation status of heavy neurofilament (NF-H), which is under the control of various intracellular kinases. While the number of Purkinje cells expressing non-phosphorylated NF-H was unchanged, the number of Purkinje cells expressing phosphorylated NF-H was decreased by 36% in the HIV group. This may be a marker of neuronal damage, and possibly indicate alteration in the activity of various intracellular signalling kinase pathways in the HIV infected brain.