Abstract
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.
Highlights
Cognitive impairment/dementia progression and its associations with diverse pathologic conditions remain mysterious
We demonstrated that the combination of Diabetes mellitus (DM) conditions and presence of Human immunodeficiency virus (HIV)-1ADA resulted in diminished blood brain barrier (BBB) tightness, which concurred with increased expression of plasmalemma vesicle associated protein (PLVAP), a marker of brain endothelial cell permeability [24,25,26] and actin cytoskeletal rearrangements
To mimic BBB injury in HIV-infected patients with DM conditions in vitro, we modeled it in the in vitro BBB model previously established in our laboratory with primary human brain endothelial cells (BMVEC) [30,31,32,33,34] using a combination of high glucose (HG) and infectious HIV-1ADA [20,35], and measured endothelial
Summary
Cognitive impairment/dementia progression and its associations with diverse pathologic conditions remain mysterious. A number of fundamental mechanisms/causes have been suggested including genetic defects in Parkinson’s disease and Alzheimer’s disease (AD), hypertension, metabolic abnormalities (diabetes mellitus (DM), homocysteinemia, toxic effects of drugs and environmental factors, etc.), chronic neuroinflammatory conditions (autoimmune or infectious origin), stroke and traumatic brain injury. HIV-1-associated neurological disorder (HAND) is described as cognitive, motor and/or behavioral deficiencies initiated by HIV replication, immune activation and neurotoxin secretion in the brain that result in neuronal damage [5]. One current theory is that HIV-1-associated neurodegeneration is forced by chronic inflammatory processes in the brain, secondary to a low level of HIV-1 replication in CNS reservoir cells (macrophages, microglia) [6,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
