Drugs May Be What's the Matter With White Matter in HIV

Some of the neurological and psychiatric complications associated with HIV may be side effects of the medications that control the virus, and not caused by the virus itself, according to a new study from researchers at The Children’s Hospital of Philadelphia and the University of Pennsylvania. Their pre-clinical findings were published in the Journal of Neuropathology and Experimental Neurology.

Certain antiretroviral drugs were associated with problems in developing myelin proteins in cell models and animal models, and the drugs were associated with reductions in white matter in autopsy brain samples from a cohort of individuals with HIV, reported the research team led by co-senior authors Judith Grinspan, PhD, research professor of Neurology at CHOP, and Kelly Jordan-Sciutto, PhD, chair and professor of Pathology at Penn’s School of Dental Medicine.

Both senior researchers emphasized that individuals with HIV should continue taking lifesaving antiretroviral drugs as prescribed. They hope their current and future findings can help researchers refine drug designs to reduce side effects, and help clinicians pursue prescribing practices that are risk-informed and tailored to the patient’s age and stage of brain development. These future changes could be particularly important for children with HIV whose brains are still developing.

For individuals with HIV, multi-drug regimens of antiretroviral treatments are lifesaving, but lifelong. These drugs have transformed the infection from a death sentence into a manageable chronic condition, and they are increasingly being prescribed to high-risk uninfected individuals as a prophylactic treatment.

Since these drugs have helped patients control their viral levels, the severe neurocognitive deficits that were often widespread among individuals with HIV have become far less common. Still, about half of HIV-infected individuals experience HIV-associated neurocognitive disorders (HAND), most of them with mild to moderate deficits.

“The question is, why were they still there when there was no obvious virus in the brain?” Dr. Grinspan said. “The antiretrovirals themselves became the suspects.”

In earlier studies, Dr. Jordan-Sciutto had found that one class of antiretroviral drugs, known as protease inhibitors, killed neurons in cell culture, and she showed the cause to be linked to drug-induced oxidative stress. The drugs had no effect on survival of astrocytes, a type of helper cell in the brain. She wondered, but was not equipped to test in her own lab, whether the drugs affected a third type of cell in the brain, oligodendrocytes.

Oligodendrocytes produce myelin, a lipid-based substance that coats and insulates neurons and constitutes the whiteness of the brain’s white matter. White matter was known to be diminished and abnormal in patients with HIV, so the role of these cells was an intriguing question.

Luckily, as Dr. Jordan-Sciutto was pondering this question a few years ago, she showed up early before delivering a talk to incoming Penn neuroscience graduate students and overheard Dr. Grinspan describing her own study of oxidative stress in oligodendrocytes. She realized that, even though Dr. Grinspan’s work had never before addressed HIV, together they could answer this question that neither of them could tackle alone. The pair successfully applied for NIH funding together, and co-advised their new paper’s first author, Brigid Jensen, PhD, during her doctoral studies.

Out of many types of antiretroviral drugs that patients receive, Dr. Jordan-Sciutto focused the team’s attention on two classes of drugs with known neurotoxicities that are most widely used around the world, and virtually universally in Africa where HIV infection is most prevalent. They tested one nucleoside reverse transcriptase inhibitor (the drug class that includes AZT) and two protease inhibitors.

In the cell-based portion of the team’s study, they applied the drugs to a model of the maturation process of oligodendrocytes from precursor cell types. They found that the protease inhibitors interfered with the cells’ maturation process. The nucleoside reverse transcriptase inhibitor had no effect.

They next treated mice to see if the drugs might affect these cells and their myelin production in a living animal.

“Myelin turns over, but slowly,” Dr. Grinspan said. “With just two weeks of these drugs we saw decreases in myelin proteins.”

Dr. Jordan-Sciutto added, “The rodent study is so important because it shows an animal without any virus had changes in myelin proteins, just from the drug treatment.”

The team was looking at adult mice, so these rapid changes in proteins reflect a potential shift in regular myelin maintenance in adult brains. Dr. Grinspan and Dr. Jordan-Sciutto pointed out that the drugs could potentially have more profound effects on brain development in immature individuals who are still developing their myelin coatings. They intend to address this question in a next phase of their research because, if the model holds for humans, the implications for children could be profound.

“The bulk of the myelin production in the human brain occurs during the first two years of life, but the process overall can take up to 20 years,” Dr. Grinspan said. “If indeed kids are exposed to drugs that stop them from myelinating, they’re going to be in trouble.”

Looking at autopsy samples of adult human brains, the researchers found further evidence of an association between antiretrovirals and loss of white matter: After controlling for factors including age, length of time on drugs, and length of time since death, HIV-infected individuals on antiretroviral therapy had alterations in several myelin proteins, especially decreases in the very important myelin basic protein, compared to uninfected individuals or compared to HIV-infected individuals who never took the drugs.

They have further work to do, both clarifying the mechanisms of how protease inhibitors affect the maturation of oligodendrocytes, and understanding the effects of the drugs on a maturing brain.

“A bonus for me as a basic developmental biologist is that in understanding the mechanisms of the drugs, we learn more about what controls oligodendrocyte differentiation,” Dr. Grinspan said. “That actually ends up being important for diseases like multiple sclerosis, which is a disease of myelin, and in cerebral palsy. Lessons we learn from HIV can affect many other conditions.”