Damage to Blood-Brain Barrier May Explain Neurocognitive Problems

HIV weakens the blood-brain barrier, which may help explain low-level cognitive impairment in people with HIV despite effective antiretroviral treatment.

Numerous studies have shown that people with HIV are more likely to experience mild-to-moderate cognitive impairment, and at an earlier age, than HIV negative people. The precise reason for this is not well understood. HIV enters the brain during early infection, but does not infect neurons.

Eliseo Eugenin from Albert Einstein College of Medicine in New York City and his colleagues have been studying astrocytes for years. These cells are an integral part of the blood-brain barrier, a network of blood vessels that protects the brain from toxins and other harmful substances. Astrocytes help to support the blood vessels that make up the barrier wall.

As described in the June 29, 2011, Journal of Neuroscience, using human cells in a laboratory model the team found that HIV infects approximately 5% of astrocytes. They saw similar results in a previous study in 2007. Infection of even this small proportion of astrocytes led to the death of others nearby, making the blood-brain barrier more porous.

The researchers next looked at structures called gap junctions that telegraph chemical signals from one astrocyte to others. They found that the HIV-infected astrocytes emit toxic signals that kill other surrounding uninfected astrocytes, compromising the integrity of the blood brain barrier. Blocking gap junctions prevented changes to the barrier, indicating that these lethal signals are transmitted via these junctions.

"This [blood-brain barrier] disruption is due to endothelial apoptosis, misguided astrocyte end feet, and dysregulation of lipoxygenase/cyclooxygenase, BKCa channels, and ATP receptor activation within astrocytes," the study authors wrote. "All of these alterations in [blood-brain barrier] integrity induced by a few HIV-infected astrocytes were gap junction dependent, as blocking these channels protected the [blood-brain barrier] from HIV-infected astrocyte-mediated compromise."

Eugenin's team performed similar experiments using brain tissue from macaque monkeys infected with simian immunodeficiency virus (a relative of HIV), and found that infected astrocytes had the same effect on surrounding cells.

"Researchers have been stymied to explain why HIV-associated neurological complications persist, despite potent combination antiviral therapies that have dramatically improved health and survival," said Igor Grant from the University of California at San Diego in a press release issued by the Society for Neuroscience, which publishes the journal. "This study provides a possible explanation indicating that minute numbers of infected astrocytes can trigger a cascade of signals that could open the brain to various toxic influences."

While antiretroviral therapy has been useful in preventing serious neurological problems such as severe dementia and meningitis, 40% to 60% of people with HIV still have low-level cognitive impairment. As people with HIV age and are at higher risk for neurocognitive decline, this research may lead to new treatment approaches to block or modify these signaling pathways that lead to cell death and weakening of the brain's protective barrier.

Investigator affiliations: Departments of Pathology and Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD.


A Eugenin, JE Clements, MC Zink, and JW Berman. Human Immunodeficiency Virus Infection of Human Astrocytes Disrupts Blood-Brain Barrier Integrity by a Gap Junction-Dependent Mechanism. Journal of Neuroscience 31(26):9456-9465 (abstract). June 29, 2011.

Other Sources

Society for Neuroscience. HIV Disrupts Blood-Brain Barrier. Press release. June 28, 2011.

Albert Einstein College of Medicine. Solving the Puzzle of Cognitive Problems Caused by HIV Infection. Press release. July 1, 2011.