HIV weakens the blood-brain barrier -- a network of blood vessels that keeps potentially harmful chemicals and toxins out of the brain -- by overtaking a small group of supporting brain cells, according to a new study in the June 29 issue of The Journal of Neuroscience. The findings may help explain why some people living with HIV experience neurological complications, despite the benefits of modern drug regimens that keep them living longer.
Standard antiretroviral treatments successfully suppress the replication of HIV and slow the progression of the disease. Yet recent studies show 40 to 60 percent of patients on such therapy continue to experience mild to moderate neurological deficits -- including memory loss and learning challenges.
In the new study, Eliseo Eugenin, PhD, of Albert Einstein College of Medicine, found that HIV infection in a small number of supporting brain cells called astrocytes breaks down the blood-brain barrier, despite low to undetectable viral production. Under normal conditions astrocytes help bolster the blood vessels comprising the barrier.
To test if HIV interfered with this support system, Eugenin and his colleagues built a model of the blood-brain barrier using human cells in the laboratory. In a previous study, the researchers found HIV infects around 5 percent of astrocytes. In the current study, the researchers found the presence of HIV in a similar percentage of astrocytes led to the death of nearby uninfected cells and made the barrier more permeable.
As the neighboring cells died, however, HIV-infected astrocytes survived. Astrocytes exchange chemical signals through specialized molecules called gap junctions. When they were blocked in the model, it prevented the changes to the blood-brain barrier and nearby cells, suggesting the infected astrocytes relay toxic signals to neighboring cells through the gap junctions.
"Our results suggest HIV infection of astrocytes may be important in the onset of cognitive impairment in people living with the disease," Eugenin said. "New therapies are needed that not only target the virus, but also to stop the virus from spreading damage to other uninfected brain cells."
Eugenin's group also analyzed the brain tissue of macaque monkeys infected with the simian form of HIV. Similar to what they saw in the human blood-brain barrier model, the researchers found uninfected cells in contact with HIV-infected astrocytes died, while infected astrocytes remained alive as the disease progressed.
"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, an expert who studies HIV-associated neurocognitive impairment at the University of California, San Diego. "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."
The findings open up the possibility of developing new therapeutic approaches that block or modify the transmission of signals from the HIV-infected astrocytes, added Grant, who was not affiliated with the study.
The research was supported by the National Institute of Mental Health.
- E. A. Eugenin, J. E. Clements, M. C. Zink, J. W. Berman. Human Immunodeficiency Virus Infection of Human Astrocytes Disrupts Blood-Brain Barrier Integrity by a Gap Junction-Dependent Mechanism. Journal of Neuroscience, 2011; 31 (26): 9456 DOI: 10.1523/JNEUROSCI.1460-11.2011
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