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HIV/AIDS medication interfere with neuronal insulation

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A type of medication for patients with HIV/AIDS, called antiretroviral therapies, or ART, has enabled those afflicted with the disease to live much longer lives. Unfortunately, around half of the patients under this kind of treatment are experiencing cognitive impairment, such as memory loss, even though
the virus is practically undetectable in their bodies.

Researchers from the University of Pennsylvania and the Children's Hospital of Philadelphia have
collaborated in order to investigate the reason as to why these cognitive impairments are occurring. They
discovered that ARTs actually hamper the activity of oligodendrocytes, which are important cells found in
the brain that produce myelin, which is the insulating material of neurons. Myelin allows neurons to
transmit signals to and from the brain effectively and efficiently.

This specific effect of ARTs on myelin may be responsible for the cognitive deficiencies that HIV patients
experience, and may therefore require reconsideration as to how HIV drugs are being administered,
especially to children who are using these drugs, as myelin is still forming at a high rate in the early stages
of human development.

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

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In order to test whether ART really affects myelin production, the researchers tested the reaction of
oligodendrocytes against the drugs. They chose three drugs, which were once the most recommended
drug combination: protease inhibitors Ritonavir and Lopinavir, along with nucleoside reverse transcriptase
inhibitor Zidovudine (AZT). They found that Ritonavir and Lopinavir reduced the oligodendrocytes' ability
to mature and make myelin, whereas AZT had no effect. Removal of the drugs from the cells resulted in
reversal of the negative effects, allowing the cells to mature and produce myelin normally. They also
tested Ritonavir on adult mice, and after two weeks of treatment, it was found that the animals had
reduced levels of mature myelin in their frontal cortex.

Lastly, the team also examined human brain tissue from HIV-infected patients provided by another
collaborator, Benjamin B. Gelman, who is from the University of Texas Medical Branch. Comparison
between HIV-positive and HIV-negative individuals revealed that there was no significant difference
between myelin levels. However, comparing these two groups to HIV-positive individuals who were
experiencing cognitive defects showed that there was a reduction in the levels of myelin basic protein
(MBP) in those who were experiencing cognitive problems.

The researchers have yet to determine the mechanism as to why ARTs cause these problems in myelin
production. Understanding the effects of drugs on oligodendrocytes could also be actually helpful in other
diseases that are oligodendrocyte-function related, such as multiple sclerosis, which manifests by a
reduction of myelin in the brain.