HIV/AIDS drugs interfere with brain's 'insulation,' study shows

December 1, 2015 by Katherine Unger Baillie, University of Pennsylvania
HIV/AIDS drugs interfere with brain’s ‘insulation,’ study shows
Oligodendrocytes (in green) failed to mature when treated with an antiretroviral drug (right panel).

Antiretroviral therapies, or ART, have enabled people with HIV and AIDS to live much longer lives, transforming what was considered a death sentence into a chronic condition. Yet concerns for these patients remain. Up to half of people with HIV on these drug regimens have some sort of cognitive impairment, such as memory loss or problems with executive functioning, despite the virus being almost undetectable in their bodies.

In a new study, researchers from the University of Pennsylvania and The Children's Hospital of Philadelphia teamed up to investigate the underlying reasons for these impairments. They found that commonly used antiretroviral medications disrupted the function of oligodendrocytes, crucial brain cells that manufacture myelin, the fatty material that serves to insulate neurons, helping them transmit signals in the brain fast and efficiently.

This disruption, the researchers said, may be responsible for some of the cognitive problems that HIV patients experience, and point to a need for rethinking how HIV drugs are designed and prescribed, particularly for children on ART, in whom myelin is still forming at high rates.

"Pharmaceutical companies have done an amazing job developing drugs to make HIV patients live longer, but we're not done," said Kelly L. Jordan-Sciutto, professor and chair of Penn's School of Dental Medicine's Department of Pathology, who co-led the research with Judith B. Grinspan, a research scientist at CHOP and a professor of neurology at Penn's Perelman School of Medicine. "The message we want to get out there is that we want to make these patients' lives better while they are on ART."

The research was published this month in the Journal of Neuropathology and Experimental Neurology.

Jordan-Sciutto struck up a collaboration with Grinspan after hearing her describing her research on oligodendrocytes. Jordan-Sciutto had previously examined the effects of ART on neurons and astrocytes. Given the fact that people on ART had been found to have reduced white matter in their brains, it made sense to investigate how oligodendrocytes would be affected, since those cells produce the lipid-filled myelin that gives white matter its characteristic color.

Myelin production is concentrated in the first two years of life, and continues throughout childhood.

"Over the first two years of life you go from having hardly any control over your body to being able to control your limbs and walk," said Grinspan. "A lot of that is on account of myelination."

But even in adults, oligodendrocytes act to ensure myelin is properly maintained.

"If myelin is destroyed, nervous impulses will no longer travel smoothly along neurons and the now bare nerve process will also start to fall apart," Grinspan said.

To see if ART could affect myelin production, the researchers decided to look at how oligodendrocytes responded to the drugs. They chose to examine three drugs that were at one time part of the most commonly recommended drug combinations prescribed to HIV patients: protease inhibitors Ritonavir and Lopinavir as well as nucleoside reverse transcriptase inhibitor Zidovudine, commonly known as AZT.

They first exposed mouse oligodendrocyte precursor cells to the three drugs at doses comparable to the concentration that would be found in plasma in an HIV patient under treatment. They found that Ritonavir and Lopinavir treatment reduced the cells' ability to mature and properly make myelin in a dose-dependent manner. AZT had no effect.

When they washed out the drugs from the cells, the effect was reversed, and oligodendrocytes were able to mature and make myelin once again.

"That told us that the drugs weren't simply killing the cells," Grinspan said. "They were creating some kind of defect that could be reversed."

Next the researchers administered Ritonavir to adult mice, selecting it because of its wide global use. After two weeks of treatment, they assessed the effect on myelin in the animals' frontal cortex and found that treated animals had significantly reduced levels of certain components of mature myelin.

Finally, the team used human brain tissue from autopsies of a cohort of HIV-infected patients provided by collaborator Benjamin B. Gelman at the University of Texas Medical Branch, to evaluate the effects of ART on myelin. They were able to sort the samples into categories based on age, whether the sample was from someone who received ART or was untreated, and whether someone had been diagnosed with a neurocognitive disorder.

They evaluated a sample of prefrontal cortex from each individual, looking for differences in myelin protein levels. When they compared the HIV-positive group to a control group of HIV-negative individuals they found no significant difference in myelin protein levels. When they specifically examined individuals who had a diagnosis of an HIV-associated neurocognitive disorder and were also on ART, they found a significant decrease in levels of the most critical myelin protein, myelin basic protein, or MBP, compared to both HIV-positive and HIV-negative groups.

The researchers have yet to determine a mechanism by which these myelin are altered with ART, but are investigating a number of avenues. They are also evaluating how different HIV medications can affect oligodendrocytes and myelin formation, as the recommended drug cocktails frequently change.

The implications of these findings may be particularly important for pediatric patients, some of whom may have been on ART from birth. Since it's known that ART treatments are associated with an increased risk of neurocognitive disorders such as autism, schizophrenia, manic depression and ADHD, the researchers stress that a revised look at treatments for pediatric patients may be warranted, or an additional therapy to prevent the loss in both adults and children could be developed to go hand in hand with the ART.

Understanding the mechanisms of the drug effects on oligodendrocytes could also shed light on the function of oligodendrocytes in other conditions, such as multiple sclerosis, which is characterized by a loss of myelin in the brain.

Explore further: New research points to potential treatment strategies for multiple sclerosis

More information: Brigid K. Jensen et al. Altered Oligodendrocyte Maturation and Myelin Maintenance, Journal of Neuropathology & Experimental Neurology (2015). DOI: 10.1097/NEN.0000000000000255

Related Stories

New research points to potential treatment strategies for multiple sclerosis

June 24, 2013
Myelin, the fatty coating that protects neurons in the brain and spinal cord, is destroyed in diseases such as multiple sclerosis. Researchers have been striving to determine whether oligodendrocytes, the cells that produce ...

Elucidation of the molecular mechanisms involved in remyelination

September 3, 2015
Researchers in Japan have revealed the molecular mechanism involved in the process of repair to damage of the myelin sheath.

New knowledge about the human brain's plasticity

November 6, 2014
The brain's plasticity and its adaptability to new situations do not function the way researchers previously thought, according to a new study published in the journal Cell. Earlier theories are based on laboratory animals, ...

How a mutated gene wreaks havoc on white matter

November 17, 2015
An inherited disease of myelin marked by slow, progressive neurological impairment is caused by mutations of a gene that controls lipid metabolism, a finding that may shed insight into mechanisms to control the course of ...

New drug target identified for multiple sclerosis and Alzheimer's disease

January 30, 2013
Researchers at Boston University School of Medicine (BUSM) led by Carmela Abraham, PhD, professor of biochemistry, along with Cidi Chen, PhD, and other collaborators, report that the protein Klotho plays an important role ...

Experimental cancer drug shows therapeutic promise in mouse models of multiple sclerosis

September 30, 2015
An experimental drug originally identified in a National Cancer Institute library of chemical compounds as a potential therapy for brain and basal cell cancers improves the symptoms of mice with a form of the debilitating ...

Recommended for you

Precision neuroengineering enables reproduction of complex brain-like functions in vitro

November 14, 2018
One of the most important and surprising traits of the brain is its ability to dynamically reconfigure the connections to process and respond properly to stimuli. Researchers from Tohoku University (Sendai, Japan) and the ...

New brain imaging research shows that when we expect something to hurt it does, even if the stimulus isn't so painful

November 14, 2018
Expect a shot to hurt and it probably will, even if the needle poke isn't really so painful. Brace for a second shot and you'll likely flinch again, even though—second time around—you should know better.

A 15-minute scan could help diagnose brain damage in newborns

November 14, 2018
A 15-minute scan could help diagnose brain damage in babies up to two years earlier than current methods.

New clues to the origin and progression of multiple sclerosis

November 13, 2018
Mapping of a certain group of cells, known as oligodendrocytes, in the central nervous system of a mouse model of multiple sclerosis (MS), shows that they might have a significant role in the development of the disease. The ...

Mutations, CRISPR, and the biology behind movement disorders

November 12, 2018
Scientists at the RIKEN Center for Brain Science (CBS) in Japan have discovered how mutations related to a group of movement disorders produce their effects. Published in Proceedings of the National Academy of Sciences, the ...

In live brain function, researchers are finally seeing red

November 12, 2018
For years, green has been the most reliable hue for live brain imaging, but after using a new high-throughput screening method, researchers at the John B. Pierce Laboratory and the Yale School of Medicine, together with collaborators ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.